Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor and method of administration thereof

ABSTRACT

A pharmaceutical gel composition for intra-intestinal administration comprises (i) a dopamine replacement agent, (ii) a dopamine decarboxylase inhibitor (DDI), and (iii) a COMT inhibitor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/054,392, filed Aug. 3, 2018, which issued as U.S. Pat. No. 10,786,472on Sep. 29, 2020, which is a divisional of U.S. patent application Ser.No. 15/507,959, filed Mar. 1, 2017, which issued as U.S. Pat. No.10,071,069 on Sep. 11, 2018, which is a national stage entry ofPCT/SE2015/050939, filed Sep. 4, 2015, which claims priority to and thebenefit of each of Sweden Patent Application No. 1451034-1, filed Sep.4, 2014 and Sweden Patent Application No. 1550344-4, filed Mar. 24,2015, the contents of all of which are herein incorporated by referencein their entireties.

BACKGROUND

Neurodegenerative disorders result when neurons normally do notreproduce or replace themselves, thus damaged neurons cannot bereplaced. Progressive degeneration and/or death of neuronal cells oftenresults in problems with movement (e.g., ataxias), or mental functioning(e.g., dementias). Many neurodegenerative disorders are currentlyconsidered to be incurable. Examples of neurodegenerative disordersinclude Parkinson's disease (“PD”), Alzheimer's disease (“AD”), andHuntington's disease (“HD”).

Parkinson's disease is characterized by a progressive degeneration ofthe dopaminergic pathway resulting in reduced concentration of theneurotransmitter dopamine in the brain which manifests itself assymptoms of slowness of movement (e.g., bradykinesia), rigidity, tremorand poor balance in the patient.

Biochemically, dopamine (3,4-dihydroxyphenethylamine) is formed bymetabolism of dopamine precursors. For example, dopamine is formed bydecarboxylation of the precursor levodopa (L-dopa;L-3,4-dihydroxyphenylalanine) through the enzyme aromatic L-amino aciddecarboxylase (also known as DOPA decarboxylase (DDC)), both in thebrain and in the peripheral circulation. Levodopa is in turn producedfrom the amino acid L-tyrosine by the enzyme tyrosine hydroxylase (TH).

Dopamine is metabolized to homovanillic acid (HVA) mainly through twometabolic pathways, namely (i) via 3,4-dihydroxyphenylacetic acid(DOPAC) by the enzymes monoamine oxidase (MAO) andcatechol-O-methyltransferase (COMT), and (ii) via 3-methoxytyramine bythe enzymes catechol-O-methyltransferase (COMT) and monoamino oxidase(MAO).

The most common treatment of PD aims at restoring the dopamineconcentration in the brain. Administration of dopamine is ineffectivebecause it does not cross the blood-brain barrier. However, since theprecursor levodopa does cross the blood-brain barrier, and is convertedto dopamine in the brain, administration of levodopa has for a long timebeen, and still is, the drug of first choice for PD treatment.

SUMMARY

The present invention provides particular compositions and strategiesfor treating certain dopamine-related diseases, disorders andconditions, including certain neurodegenerative disorders (e.g.,Parkinson's Disease (PD)) and/or for administering agents useful in suchtreatment. Among other things, the present invention encompassesidentification of the source of a problem with certain knowncompositions and/or strategies for treating such diseases, disorders orconditions and/or for administering relevant agents.

In some embodiments, the present disclosure encompasses the insight thatadministering a combination of agents that includes each of (i) adopamine replacement agent, (ii) a dopamine decarboxylase inhibitor(DDI), and (iii) a COMT inhibitor to a subject, particularly when one ormore of the agents is delivered by intra-intestinal administration of apharmaceutical gel, provides certain unexpected advantages and/or solvesone or more problems associated with prior strategies for treatingneurodegenerative disorders (e.g., PD).

In some embodiments, the present disclosure provides methods in which aCOMT inhibitor is administered in combination with therapy that involvesadministering a dopamine replacement agent and/or a DDI byintra-intestinal administration of a pharmaceutical gel.

In some embodiments, the present invention encompasses the insight thatin various contexts may be useful to deliver a COMT inhibitor byintra-intestinal administration of a pharmaceutical gel, and providesparticular methods and reagents relating thereto.

Among other things, the present invention encompasses identification ofthe source of a problem with certain known compositions and/orstrategies for administering a dopamine replacement agent (e.g.,levodopa). For example, the present disclosure encompasses therecognition of a need for treatment strategies that minimize a subject'sintake of and/or exposure to the metabolic precursor, while maintainingtherapeutic benefit of such intake or exposure. The present disclosureprovides such treatment strategies (e.g., compositions and/or methodsthat achieve reduced patient exposure, while maintaining therapeuticbenefit, as compared with a relevant reference strategy (e.g., acurrently accepted standard therapy).

In some embodiments, the present disclosure encompasses the recognitionof a need for improved pharmaceutical compositions for intra-intestinaladministration of a dopamine replacement agent, and particularly oflevodopa. The present disclosure provides such compositions.

In some embodiments, the present disclosure identifies the source of aproblem with storage characteristics (e.g., stability to long termstorage and/or storage under particular conditions) of certaincompositions comprising a dopamine replacement agent, and particularlyof compositions comprising levodopa. Among other things, the presentdisclosure encompasses the recognition of a need for pharmaceuticalcompositions comprising dopamine replacement agents, and particularly ofcompositions comprising levodopa, which have particular storagestability characteristics. The present disclosure provides suchcompositions.

In many embodiments, intra-intestinal administration typically isduodenal and/or jejunal administration via an external access point.

In some embodiments, a pharmaceutical gel composition forintra-intestinal administration comprises a dopamine replacement agent,a dopamine decarboxylase inhibitor (DDI), and acatechol-O-methyltransferase (COMT) inhibitor.

In some particular embodiments, the present invention provides apharmaceutical gel composition for intra-intestinal administration,comprising at least about 10 mg/ml of levodopa and at least about 2.5mg/ml of a dopamine decarboxylase inhibitor, wherein the gel compositionfurther comprises at least about 10 mg/ml of a COMT inhibitor.

In certain provided gel compositions and/or methods, one or more activecompounds (e.g., levodopa and/or one or more DDIs [e.g., carbidopa]and/or one or more COMT inhibitors [e.g., entacapone]) may be providedand/or utilized in the form of a pharmaceutically acceptable saltthereof, and/or in a hydrate or solvate form thereof. In some particularembodiments, certain compositions and/or methods may utilize one or moreactive compounds may be provided and/or utilized in a solid form; insome such embodiments, the solid form may be or comprise a crystallineform; in some such embodiments, the solid form may be or comprise anamorphous form. In some embodiments, a solid form comprises or consistsof an amorphous form, or a single particular crystalline form.

In some embodiments, a pharmaceutical gel composition comprises at most200 mg/ml of levodopa, at most 50 mg/ml of a dopamine decarboxylaseinhibitor, and at most 200 mg/ml of a COMT inhibitor.

Exemplary dopamine decarboxylase inhibitors include carbidopa,benzerazide, α-difluoromethyldopa[(2S)-2-amino-2-[3,4-dihydroxyphenyl)-methyl]-3,3-difluoropropanoicacid] and α-methyldopa[(S)-2-amino-3-[3,4-dihydroxyphenyl)-2-methyl-propanoic acid].

In some embodiments, a dopamine decarboxylase inhibitor is carbidopa,benserazide, or any combination thereof.

In some embodiments, a dopamine decarboxylase inhibitor is carbidopa.

In some embodiments, a COMT inhibitor is selected from the groupconsisting of entacapone, tolcapone, opicapone and any combinationthereof.

In some embodiments, a COMT inhibitor is entacapone.

In some embodiments, a pharmaceutical gel composition comprises a DDIsuch as carbidopa, and further comprises a substance capable ofinhibiting degradation of carbidopa to hydrazine.

In some embodiments, a substance capable of inhibiting degradation ofcarbidopa to hydrazine comprises entacapone.

In some embodiments, a pharmaceutical gel composition comprises about 20mg/ml of levodopa, 5 mg/ml of carbidopa, and 20 mg/ml of entacapone.

In some embodiments, a pharmaceutical gel composition as describedherein that comprises one or more COMT inhibitors and at least oneadditional active compound is characterized by increased stability(e.g., reduced degradation) of the at least one additional activecompound, for example relative to that observed for an otherwisecomparable composition lacking (or, in some embodiments, containing adifferent absolute or relative amount of) the COMT inhibitor. In somesuch embodiments, stability is assessed over time (e.g., after aparticular period of time has elapsed) and/or under particular storageconditions. For example, in some embodiments, such increased stabilityis observed over a period of time that extends for at least 1 week, 2weeks, 5 weeks, 7 weeks, 10 weeks, 15 weeks, 20 weeks or more, forexample under refrigerated conditions (e.g., conditions under which thecomposition(s) is/are maintained at a temperature below about 15° C.and, preferably, within a range of about 0° C. to about 15° C., about 0°C. to about 12° C., about 0° C. to about 10° C., about 0° C. to about 8°C., or about 2° C. to about 8° C.).

In some embodiments, a provided intra-intestinal gel compositioncomprises and/or is prepared from a gel characterized by a pH not higherthan about 5.7 and/or is maintained at a pH not higher than about 5.7.In some embodiments, such provided compositions that include one or moreactive agents (e.g., levodopa, a DDI, a COMT inhibitor, etc.) arecharacterized by improved stability of one or more such active agents ascompared with a relevant reference composition that differs, forexample, in value of pH.

In some embodiments, an intra-intestinal gel composition is deoxygenized(e.g., via nitrogen purging). In some embodiments, such providedcompositions that include one or more active agents are characterized byimproved stability of one or more such active agents as compared with arelevant reference composition that differs, for example, in presenceand/or duration of such deoxygenization.

In some embodiments, a pharmaceutical gel composition includesantioxidants (e.g., ascorbic acid or citric acid). In some embodiments,such provided compositions that include one or more active agents arecharacterized by improved stability of one or more such active agents ascompared with a relevant reference composition that differs, forexample, in presence and/or amount (e.g., absolute or relative values)of such antioxidants.

In some embodiments, deoxygenation is combined with lowered pH orantioxidant.

In some embodiments, a provided gel composition is substantially free of(e.g., lacks detectable and/or material levels of) a metal chelatingagent, such as EDTA; in some embodiments, a provided gel composition issubstantially free of any metal chelating agent.

In some embodiments, a pharmaceutical gel composition is provided in alight-protected container.

In some embodiments, one or more active substances, (e.g., levodopa,dopamine carboxylase inhibitor (e.g., carbidopa) and COMT inhibitor(e.g., entacapone) are in the form of particles, for example having amaximum particle size not exceeding about 80 μm, which particles may, insome embodiments, be suspended in a carrier (e.g., in an aqueouscarrier); in some such embodiments, the carrier has a viscosity of atleast 300 mPas, measured at a moderate shear rate.

In some embodiments, viscosity of an intra-intestinal gel composition isat least 1800 mPas. In another embodiment, the viscosity is in the rangeof 2200 to 4500 mPas.

While a carrier typically may be of polysaccharide type, and, forexample, be selected from cellulose, methyl cellulose (MC), ethylcellulose, carboxymethyl cellulose (CMC) and salts thereof, xanthan gum,carrageenan, and combinations thereof the carrier may also be asynthetic polymer, such as polyvinylpyrrolidone (PVP; Povidon) orpolyacrylic acid (PAA; Carbomer). An exemplary carrier is the sodiumsalt of carboxymethyl cellulose (NaCMC).

In some embodiments, a pharmaceutical gel composition comprises about 2%(w/w) micronized levodopa, about 0.5% (w/w) micronized carbidopa, 2about % (w/w) micronized entacapone, and 2.92 about % (w/w) sodiumcarboxymethyl cellulose.

In some embodiments, a pH value of a pharmaceutical gel composition isselected to be the lowest pH value equal to or greater than about 5.0 toabout 5.5 where viscosity of an aqueous carrier after 12 days at 25° C.is at least 300 mPas at a moderate shear rate.

In some embodiments, a carrier of a pharmaceutical gel composition isNaCMC, and the pH value is 5.5±0.2.

In some aspects of the present invention provides a pharmaceutical gelcomposition for a treatment of neurodegenerative disorders (e.g.,Parkinson's Disease).

In some aspects of the present invention, there is provided a method oftreating Parkinson's Disease, which comprises intra-intestinallyadministering a pharmaceutical gel composition according to certainaspects of the present invention as described above.

In some embodiments, a pharmaceutical gel composition is administeredcontinuously over a period less than about 16 hours per day.

In some embodiments, a pharmaceutical gel composition is administeredcontinuously over a period greater than about 16 hours per day.

In some embodiments, a pharmaceutical gel composition is administeredcontinuously as a long-term treatment for more than 1 day.

In some aspects, the present invention provides use of entacapone in apharmaceutical gel composition comprising levodopa and carbidopa forinhibiting degradation of carbidopa to hydrazine.

In some embodiments, a pharmaceutical gel composition comprises apharmaceutically active agent and formulated for intra-intestinaldelivery, wherein the pharmaceutically active agent is or comprisesentacapone.

In some embodiments, a pharmaceutical gel composition forintra-intestinal administration comprises levodopa, a dopaminedecarboxylase inhibitor and a COMT inhibitor, wherein the weight ratioof the COMT inhibitor to the dopamine decarboxylase inhibitor is about10:1 to about 2:1, or about 5:1 to about 3:1.

In some embodiments, a pharmaceutical gel composition forintra-intestinal administration comprises levodopa, a dopaminedecarboxylase inhibitor, and a COMT inhibitor, wherein the weight ratioof the dopamine decarboxylase inhibitor to levodopa is at least about1:10.

In some embodiments, a pharmaceutical gel composition forintra-intestinal administration comprises levodopa, a dopaminedecarboxylase inhibitor, and a COMT inhibitor, wherein the levodopa, thedopamine decarboxylase inhibitor and the COMT inhibitor are in the formof particles, and the particles are suspended in an aqueous carrier, andhave the particle size of no greater than about 80 μm.

In some embodiments, a method of prolonging shelf life of apharmaceutical gel comprises providing a first gel comprising levodopaand a dopamine decarboxylase inhibitor and including a COMT inhibitor inthe first gel.

In some embodiments, a method for reducing hydrazine production and/oraccumulation in a pharmaceutical composition comprise levodopa andcarbidopa and/or upon its administration comprises a step of including aCOMT inhibitor in the pharmaceutical compositions.

Some embodiments are set forth in the dependent claims.

A more complete understanding of the invention, as well as furtherfeatures and advantages thereof, will be obtained by reference to thefollowing detailed description read in conjunction with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing an exemplary level of carbidopa degradationproduct DHPA versus pH at the end of a 10 days stability test at 25° C.on a levodopa/carbidopa/entacapone gel formulation.

FIG. 2 is a graph showing an exemplary level of carbidopa degradationproduct DHPPA versus pH at the end of a 10 days stability test at 25° C.on a levodopa/carbidopa/entacapone gel formulation.

FIG. 3 is a graph showing an exemplary level of entacapone degradationproduct RRT 11.8 versus pH at the end of a 10 days stability test on alevodopa/carbidopa/entacapone gel formulation.

FIG. 4 is a graph showing an exemplary level of reduced viscosity versuspH at the end of a 12 days stability test on alevodopa/carbidopa/entacapone gel formulation.

FIG. 5 is a graph showing exemplary levels of carbidopa degradationproduct hydrazine during a 20 weeks storage stability test inrefrigerated condition (2-8° C.) on a levodopa/carbidopa gel formulation(upper curve) and a levodopa/carbidopa/entacapone gel formulation (lowercurve).

FIG. 6 is a graph showing exemplary levels of carbidopa degradationproduct hydrazine during a 20 weeks storage stability test inrefrigerated condition (2-8° C.) on two levodopa/carbidopa/entacaponegel formulations of different pH; upper curve pH 5.5 and lower curve pH5.0.

FIG. 7 is a graph showing exemplary pharmacokinetic studies of LECIGON™vs DUODOPA®. Y-axis depicts LECIGON™'s Area Under Curve (AUC) increaseper dose of levodopa compared to DUODOPA® (i.e., bioavailabilityincrease). X-axis depicts levodopa dose of LECIGON™.

DEFINITIONS

As used herein, the term “activating agent” refers to an agent whosepresence or level correlates with elevated level or activity of atarget, as compared with that observed absent the agent (or with theagent at a different level). In some embodiments, an activating agent isone whose presence or level correlates with a target level or activitythat is comparable to or greater than a particular reference level oractivity (e.g., that observed under appropriate reference conditions,such as presence of a known activating agent, e.g., a positive control).

As used herein, the term “administration” refers to the administrationof a composition to a subject or system. Administration to an animalsubject (e.g., to a human) may be by any appropriate route. For example,in some embodiments, administration may be bronchial (including bybronchial instillation), buccal, enteral, interdermal, intra-arterial,intradermal, intragastric, intramedullary, intramuscular, intranasal,intraperitoneal, intrathecal, intravenous, intraventricular, within aspecific organ (e.g. intrahepatic), mucosal, nasal, oral, rectal,subcutaneous, sublingual, topical, tracheal (including by intratrachealinstillation), transdermal, vaginal and vitreal. In some embodiments,administration may involve intermittent dosing. In some embodiments,administration may involve continuous dosing (e.g., perfusion) for atleast a selected period of time. As is known in the art, antibodytherapy is commonly administered parenterally (e.g., by intravenous orsubcutaneous injection).

As used herein, the term “approximately” or “about,” as applied to oneor more values of interest, refers to a value that is similar to astated reference value. In certain embodiments, the term “approximately”or “about” refers to a range of values that fall within 25%, 20%, 19%,18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%,2%, 1%, or less in either direction (greater than or less than) of thestated reference value unless otherwise stated or otherwise evident fromthe context (except where such number would exceed 100% of a possiblevalue).

Two events or entities are “associated” with one another, as that termis used herein, if the presence, level and/or form of one is correlatedwith that of the other. For example, a particular entity (e.g.,polypeptide, genetic signature, metabolite, etc.) is considered to beassociated with a particular disease, disorder, or condition, if itspresence, level and/or form correlates with incidence of and/orsusceptibility to the disease, disorder, or condition (e.g., across arelevant population). In some embodiments, two or more entities arephysically “associated” with one another if they interact, directly orindirectly, so that they are and/or remain in physical proximity withone another. In some embodiments, two or more entities that arephysically associated with one another are covalently linked to oneanother; in some embodiments, two or more entities that are physicallyassociated with one another are not covalently linked to one another butare non-covalently associated, for example by means of hydrogen bonds,van der Waals interaction, hydrophobic interactions, magnetism, andcombinations thereof.

As used herein, the term “carrier” refers to a diluent, adjuvant,excipient, or vehicle with which a composition is administered. In someexemplary embodiments, carriers can include sterile liquids, such as,for example, water and oils, including oils of petroleum, animal,vegetable or synthetic origin, such as, for example, peanut oil, soybeanoil, mineral oil, sesame oil and the like. In some embodiments, carriersare or include one or more solid components.

As used herein, the term “combination therapy” refers to thosesituations in which a subject is simultaneously exposed to two or moretherapeutic regimens (e.g., two or more therapeutic agents). In someembodiments, two or more agents or may be administered simultaneously;in some embodiments, such agents may be administered sequentially; insome embodiments, such agents are administered in overlapping dosingregimens.

A “composition” or a “pharmaceutical composition” according to thisinvention refers to the combination of two or more agents as describedherein for co-administration or administration as part of the sameregimen. It is not required in all embodiments that the combination ofagents result in physical admixture, that is, administration as separateco-agents each of the components of the composition is possible; howevermany patients or practitioners in the field may find it advantageous toprepare a composition that is an admixture of two or more of theingredients in a pharmaceutically acceptable carrier, diluent, orexcipient, making it possible to administer the component ingredients ofthe combination at the same time.

As used herein, the term “comparable” refers to two or more agents,entities, situations, sets of conditions, etc., that may not beidentical to one another but that are sufficiently similar to permitcomparison there between so that conclusions may reasonably be drawnbased on differences or similarities observed. In some embodiments,comparable sets of conditions, circumstances, individuals, orpopulations are characterized by a plurality of substantially identicalfeatures and one or a small number of varied features. Those of ordinaryskill in the art will understand, in context, what degree of identity isrequired in any given circumstance for two or more such agents,entities, situations, sets of conditions, etc to be consideredcomparable. For example, those of ordinary skill in the art willappreciate that sets of circumstances, individuals, or populations arecomparable to one another when characterized by a sufficient number andtype of substantially identical features to warrant a reasonableconclusion that differences in results obtained or phenomena observedunder or with different sets of circumstances, individuals, orpopulations are caused by or indicative of the variation in thosefeatures that are varied.

The term “dopamine replacement agent”, as used herein, refers to anagent whose administration to a human, correlates with increaseddopamine levels in the brain as compared with those observed absent suchadministration. In some embodiments, a dopamine replacement agent ischaracterized by an ability to cross the blood-brain barrier. In someembodiments, a dopamine replacement agent is selected from the groupconsisting of metabolic precursors of dopamine (e.g., levodopa,melevodopa, etilevodopa etc and combinations thereof), dopamine agonists(e.g., apomorphine, bromocriptine, cabergoline, dihydroergocristinemesylate, pergolide, piribedil pramipexole, ropinirole, rotigotine, etcand combinations thereof), agents that block dopamine degradation (e.g.,MAO-B inhibitors such as selegiline, rasagiline, etc. and combinationsthereof) and/or agents (e.g., budipine) that otherwise stimulatedopamine production. Various commercial formulations and preparations ofsuch agents are known in the art, including certain oral (e.g., capsuleor tablet), transdermal (e.g., patch), parenteral (e.g., subcutaneous,intravenous, intrathecal, etc., particularly for infusion), and/or other(e.g., gel, and particularly intra-intestinal gel) formulations.

As used herein, the term “dosage form” refers to a physically discreteunit of an active agent (e.g., a therapeutic or diagnostic agent) foradministration to a subject. Each unit contains a predetermined quantityof active agent. In some embodiments, such quantity is a unit dosageamount (or a whole fraction thereof) appropriate for administration inaccordance with a dosing regimen that has been determined to correlatewith a desired or beneficial outcome when administered to a relevantpopulation (i.e., with a therapeutic dosing regimen). Those of ordinaryskill in the art appreciate that the total amount of a therapeuticcomposition or agent administered to a particular subject is determinedby one or more attending physicians and may involve administration ofmultiple dosage forms.

As used herein, the term “dosing regimen” refers to a set of unit doses(typically more than one) that are administered individually to asubject, typically separated by periods of time. In some embodiments, agiven therapeutic agent has a recommended dosing regimen, which mayinvolve one or more doses. In some embodiments, a dosing regimencomprises a plurality of doses each of which are separated from oneanother by a time period of the same length; in some embodiments, adosing regimen comprises a plurality of doses and at least two differenttime periods separating individual doses. In some embodiments, all doseswithin a dosing regimen are of the same unit dose amount. In someembodiments, different doses within a dosing regimen are of differentamounts. In some embodiments, a dosing regimen comprises a first dose ina first dose amount, followed by one or more additional doses in asecond dose amount different from the first dose amount. In someembodiments, a dosing regimen comprises a first dose in a first doseamount, followed by one or more additional doses in a second dose amountsame as the first dose amount In some embodiments, a dosing regimen iscorrelated with a desired or beneficial outcome when administered acrossa relevant population (i.e., is a therapeutic dosing regimen).

As used herein, the term “excipient” refers to a non-therapeutic agentthat may be included in a pharmaceutical composition, for example toprovide or contribute to a desired consistency or stabilizing effect.Suitable pharmaceutical excipients include, for example, starch,glucose, lactose, sucrose, gelatine, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike.

As used herein, the term “gel” refers to a viscoelastic material whoserheological properties distinguish it from, for example, a solution, asolid, etc. In some embodiments, a material or composition is consideredto be a gel if its storage modulus (G′) is larger than its modulus (G″).In some embodiments, a composition is considered to be a gel if thereare chemical or physical cross-linked networks in solution, for exampleas distinguished from entangled molecules in viscous solution. In someembodiments, a gel composition may be or comprise particles of a firstmaterial suspended or otherwise distributed within a matrix. In someembodiments, a matrix is or comprises polysaccharide type, and, forexample, be selected from cellulose, methyl cellulose (MC), ethylcellulose, carboxymethyl cellulose (CMC) and salts thereof, xanthan gum,carrageenan, and combinations thereof the carrier may also be asynthetic polymer, such as polyvinylpyrrolidone (PVP; Povidon) orpolyacrylic acid (PAA; Carbomer). An exemplary carrier is the sodiumsalt of carboxymethyl cellulose (NaCMC).

As used herein, the term “patient” refers to any organism to which aprovided composition is or may be administered, e.g., for experimental,diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typicalpatients include animals (e.g., mammals such as mice, rats, rabbits,non-human primates, and/or humans). In some embodiments, a patient is ahuman. In some embodiments, a patient is suffering from or susceptibleto one or more disorders or conditions (e.g., a dopamine-relateddisease, disorder or condition, for example a neurodegenerative disordersuch as PD). In some embodiments, a patient displays one or moresymptoms of a disease, disorder or condition. In some embodiments, apatient has been diagnosed with one or more diseases, disorders orconditions. In some embodiments, the patient is receiving or hasreceived certain therapy to diagnose and/or to treat a disease,disorder, or condition.

As used herein, the term “pharmaceutical composition” refers to acomposition in which an active agent is formulated together with one ormore pharmaceutically acceptable carriers. In some embodiments, activeagent is present in unit dose amount appropriate for administration in atherapeutic regimen that shows a statistically significant probabilityof achieving a predetermined therapeutic effect when administered to arelevant population. In some embodiments, pharmaceutical compositionsmay be specially formulated for administration in solid or liquid form,including those adapted for the following: oral administration, forexample, drenches (aqueous or non-aqueous solutions or suspensions),tablets, e.g., those targeted for buccal, sublingual, and systemicabsorption, boluses, powders, granules, pastes for application to thetongue; parenteral administration, for example, by subcutaneous,intramuscular, intravenous or epidural injection as, for example, asterile solution or suspension, or sustained-release formulation;topical application, for example, as a cream, ointment, or acontrolled-release patch or spray applied to the skin, lungs, or oralcavity; intravaginally or intrarectally, for example, as a pessary,cream, or foam; sublingually; ocularly; transdermally; or nasally,pulmonary, and to other mucosal surfaces.

The term “shear rate” as used herein refers to a rate at which aprogressive deformation of a material substance in which parallelinternal surfaces slide past one another is applied to some material. A“moderate shear rate” as used herein refers to the shear rate when theaqueous carrier is moderately agitated, typically corresponding to ashear rate of less than approximately 500 s⁻¹ but higher thanapproximately 20 s⁻¹ where the carrier is almost at rest.

The term “stable,” when applied to compositions herein, means that thecompositions maintain one or more aspects of their physical structureand/or activity over a period of time under a designated set ofconditions. In some embodiments, the period of time is at least aboutone hour; in some embodiments the period of time is about 5 hours, about10 hours, about one (1) day, about one (1) week, about two (2) weeks,about one (1) month, about two (2) months, about three (3) months, aboutfour (4) months, about five (5) months, about six (6) months, abouteight (8) months, about ten (10) months, about twelve (12) months, abouttwenty-four (24) months, about thirty-six (36) months, or longer. Insome embodiments, the period of time is within the range of about one(1) day to about twenty-four (24) months, about two (2) weeks to abouttwelve (12) months, about two (2) months to about five (5) months, etc.In some embodiments, the designated conditions are ambient conditions(e.g., at room temperature and ambient pressure). In some embodiments,the designated conditions are physiologic conditions (e.g., in vivo orat about 37° C. for example in serum or in phosphate buffered saline).In some embodiments, the designated conditions are under cold storage(e.g., at or below about 4° C., −20° C., or −70° C.). In someembodiments, the designated conditions are in the dark.

As used herein, the term “substantially” refers to the qualitativecondition of exhibiting total or near-total extent or degree of acharacteristic or property of interest. One of ordinary skill in thebiological arts will understand that biological and chemical phenomenararely, if ever, go to completion and/or proceed to completeness orachieve or avoid an absolute result. The term “substantially” istherefore used herein to capture the potential lack of completenessinherent in many biological and chemical phenomena.

As used herein, the phrase “therapeutic agent” or “active agent” (e.g.,“active compound”) in general refers to any agent that elicits a desiredpharmacological effect when administered to an organism. In someembodiments, an agent is considered to be a therapeutic agent if itdemonstrates a statistically significant effect across an appropriatepopulation. In some embodiments, the appropriate population may be apopulation of model organisms. In some embodiments, an appropriatepopulation may be defined by various criteria, such as a certain agegroup, gender, genetic background, preexisting clinical conditions, etc.In some embodiments, a therapeutic agent is a substance that can be usedto alleviate, ameliorate, relieve, inhibit, prevent, delay onset of,reduce severity of, and/or reduce incidence of one or more symptoms orfeatures of a disease, disorder, and/or condition. In some embodiments,a “therapeutic agent” is an agent that has been or is required to beapproved by a government agency before it can be marketed foradministration to humans. In some embodiments, a “therapeutic agent” isan agent for which a medical prescription is required for administrationto humans.

As used herein, the term “therapeutically effective amount” is meant anamount that produces the desired effect for which it is administered. Insome embodiments, the term refers to an amount that is sufficient, whenadministered to a population suffering from or susceptible to a disease,disorder, and/or condition in accordance with a therapeutic dosingregimen, to treat the disease, disorder, and/or condition. In someembodiments, a therapeutically effective amount is one that reduces theincidence and/or severity of, and/or delays onset of, one or moresymptoms of the disease, disorder, and/or condition. Those of ordinaryskill in the art will appreciate that the term “therapeuticallyeffective amount” does not in fact require successful treatment beachieved in a particular individual. Rather, a therapeutically effectiveamount may be that amount that provides a particular desiredpharmacological response in a significant number of subjects whenadministered to patients in need of such treatment. In some embodiments,reference to a therapeutically effective amount may be a reference to anamount as measured in one or more specific tissues (e.g., a tissueaffected by the disease, disorder or condition) or fluids (e.g., blood,saliva, serum, sweat, tears, urine, etc.). Those of ordinary skill inthe art will appreciate that, in some embodiments, a therapeuticallyeffective amount of a particular agent or therapy may be formulatedand/or administered in a single dose. In some embodiments, atherapeutically effective agent may be formulated and/or administered ina plurality of doses, for example, as part of a dosing regimen.

As used herein, the term “treatment” (also “treat” or “treating”) refersto any administration of a substance (e.g., anti-receptor tyrosinekinases antibodies or receptor tyrosine kinase antagonists) thatpartially or completely alleviates, ameliorates, relives, inhibits,delays onset of, reduces severity of, and/or reduces incidence of one ormore symptoms, features, and/or causes of a particular disease,disorder, and/or condition (e.g., cancer). Such treatment may be of asubject who does not exhibit signs of the relevant disease, disorderand/or condition and/or of a subject who exhibits only early signs ofthe disease, disorder, and/or condition. Alternatively or additionally,such treatment may be of a subject who exhibits one or more establishedsigns of the relevant disease, disorder and/or condition. In someembodiments, treatment may be of a subject who has been diagnosed assuffering from the relevant disease, disorder, and/or condition. In someembodiments, treatment may be of a subject known to have one or moresusceptibility factors that are statistically correlated with increasedrisk of development of the relevant disease, disorder, and/or condition.

The expression “unit dose” as used herein refers to an amountadministered as a single dose and/or in a physically discrete unit of apharmaceutical composition. In many embodiments, a unit dose contains apredetermined quantity of an active agent. In some embodiments, a unitdose contains an entire single dose of the agent. In some embodiments,more than one unit dose is administered to achieve a total single dose.In some embodiments, administration of multiple unit doses is required,or expected to be required, in order to achieve an intended effect. Aunit dose may be, for example, a volume of liquid (e.g., an acceptablecarrier) containing a predetermined quantity of one or more therapeuticagents, a predetermined amount of one or more therapeutic agents insolid form, a sustained release formulation or drug delivery devicecontaining a predetermined amount of one or more therapeutic agents,etc. It will be appreciated that a unit dose may be present in aformulation that includes any of a variety of components in addition tothe therapeutic agent(s). For example, acceptable carriers (e.g.,pharmaceutically acceptable carriers), diluents, stabilizers, buffers,preservatives, etc., may be included as described infra. It will beappreciated by those skilled in the art, in many embodiments, a totalappropriate daily dosage of a particular therapeutic agent may comprisea portion, or a plurality, of unit doses, and may be decided, forexample, by the attending physician within the scope of sound medicaljudgment. In some embodiments, the specific effective dose level for anyparticular subject or organism may depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;activity of specific active compound employed; specific compositionemployed; age, body weight, general health, sex and diet of the subject;time of administration, and rate of excretion of the specific activecompound employed; duration of the treatment; drugs and/or additionaltherapies used in combination or coincidental with specific compound(s)employed, and like factors well known in the medical arts.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The following description is for illustration and exemplification of theinvention only and is not intended to limit the invention to thespecific embodiments described.

Unless defined otherwise, technical and scientific terms have the samemeaning as commonly understood by one of ordinary skill in the art towhich this invention belongs.

All references cited herein, including patent applications andpublications, are incorporated by reference in their entirety.

As mentioned above, the present invention relates to novelpharmaceutical compositions and/or methodologies for treating certaindopamine-related diseases, disorders and conditions. In manyembodiments, the present invention relates to compositions and/ormethodologies for treating neurodegenerative diseases (e.g., Parkinson'sDisease), in the following frequently referred to as PD). In particular,the present invention relates to intra-intestinal (typically duodenal orjejunal) administration of dopamine replacement agents, a COMT inhibitor(e.g., entacapone, opicapone, tolcapone, etc., and combinationsthereof), together with a dopamine replacement agent (e.g., levodopa,melevodopa, etilevodopa, budipine and combinations thereof) and adopamine decarboxylase inhibitor (e.g., carbidopa, benserazide, andcombinations thereof), in the context of a pharmaceutical compositionthat is characterized by being in gel form. In many embodiments, allthree components are administered intra-intestinally, and often in thesame composition (i.e., in the same unit dosage form).

Dopamine-Related Diseases, Disorders, and Conditions

In many embodiments, the present disclosure relates to treatment of oneor more dopamine-related diseases, disorders, or conditions. In someembodiments, the present disclosure particularly relates to treatment oflevodopa-responsive patients.

As noted above, dopamine is a neurotransmitter. Dopamine plays a numberof important roles in the nervous system, and several importantdiseases, disorders and conditions are associated with dysfunction inthe dopamine system. In some embodiments, a dopamine-related disease,disorder or condition may be associated with and altered level and/oractivity of dopamine in one or more relevant nervous system areas ortissues (e.g., in the brain or a particular region thereof) relative tothat observed absent the disease, disorder or condition. In manyembodiments, such an altered level is a decreased level.

Exemplary dopamine-related diseases, disorders and conditions mayinclude albinism, Alzheimer's disease, amblyopia, angelman syndrome,anterior ischemic optic neuropathy, aphasia, back pain, depression,dopamine beta-hydroxylase deficiency, drug (e.g., alcohol, cocaine,opiate) dependence/abuse, dyslexia, dystonic cerebral palsy,Huntington's disease, hypotensive syncope, impulse control disorder,medullary carcinoma, motor neuron disease, movement disorders,multisystemic atrophy, orthostatic hypotension, orthostatic intolerance,Parkinson's disease, prion disease, restless legs syndrome, retinaldiseases, schizophrenia, spinal cord injury, spinal muscular atrophy,spinocerebellar ataxia, stroke, thyroid carcinoma, thyroid neoplasm,tourette syndrome, etc.

In some embodiments, dopamine-related disease, disorder or conditionsmay be or comprise one or more proliferative disorders (e.g., cancers),inflammatory conditions, neurodegenerative diseases, etc., andcombinations thereof.

In many embodiments, dopamine-related diseases, disorders or conditionsare neurodegenerative disorders (e.g., PD, AD, HD).

Embodiments of the present disclosure are particularly relevant fortreatment of PD. In general, a patient to which therapy as describedherein is administered may be in any phase of PD. In many embodiments,however, a PD patient is in a moderate to advanced phase, for exampleconsistent with Hoehn and Yahr (H&Y) stage II or higher. In someembodiments, a PD patient is experiencing motor fluctuations andhyper-/dyskinesia. In some embodiments, a PD patient has received priortherapy with one or more conventional treatments as described herein(e.g., that involve intermittent dosing and/or patient exposure toactive agent(s)). In some particular embodiments, a PD patient may havereceived prior oral levodopa therapy and be experiencing motorfluctuations. In some embodiments, the present disclosure proposes thatsuch motor fluctuations may result, at least to some extent, frompulsatile dopaminergic stimulation, in some situations compounded byshort half-life and/or erratic absorption (e.g., as can result fromgastric emptying) of oral levodopa therapy. In some aspects, the presentdisclosure provides the insight that certain compositions providedherein (including specifically certain gel compositions forintra-intestinal administration that include as active agents each of(a) a dopamine replacement agent; (b) a DDI; and (c) a COMT inhibitor)can provide various advantages in the treatment of such patients.Without wishing to be bound by any particular theory, it is proposedthat such compositions may achieve substantially continuous dopaminergicstimulation in these (and other) patients, thereby improving therapeuticoutcome and, in particular, reducing risk of developing or worseningmotor fluctuations.

The patient can be treated with some few tablets per day but istypically receiving a cocktail of anti-Parkinson medications. Thepatient can also be treated with a more continuous dopaminergicstimulation such as Levodopa Carbidopa Intestinal Gel (DUODOPA®,DUOPA®), Apomorphine, DBS and/or patch or a combination thereof.

Current recommended therapy for dopamine-related diseases, disorder, andconditions often includes administration of dopamine, of a precursorcompound (e.g., levodopa, melevodopa, etilevodopa) that is metabolicallyconverted to dopamine after administration, or of another type ofdopamine replacement agent. In particular, the metabolic precursorlevodopa is commonly administered in the treatment neurodegenerativedopamine-related diseases, disorders or conditions, particularly such asPD.

Dopamine Replacement Agents

As noted above, many dopamine-related diseases, disorders and conditionsare associated with decreased dopamine levels in one or more relevanttissues or sites. Recommended therapy often includes administration ofdopamine, or of a precursor compound that is metabolically converted todopamine after administration. In particular, given that dopamine doesnot cross the blood-brain barrier, alternative agents that do areparticularly desirable for treatment of neurodegenerativedopamine-related diseases, disorders or conditions, particularly such asPD. Such agents are referred to herein as “dopamine replacement agents”and include, for example, metabolic precursors of dopamine (e.g.,levodopa, melevodopa, etilevodopa, etc. and combinations thereof),dopamine agonists (e.g., apomorphine, bromocriptine, cabergoline,dihydroergocristine mesylate, pergolide, piribedil pramipexole,ropinirole, rotigotine, etc. and combinations thereof), agents thatblock dopamine degradation (e.g., MAO-B inhibitors such as selegiline,rasagiline, etc., and combinations thereof) and/or agents (e.g.,budipine) that otherwise stimulate dopamine production. Variouscommercial formulations and preparations of such agents are known in theart, including certain oral (e.g., capsule or tablet), transdermal(e.g., patch), parenteral (e.g., subcutaneous, intravenous, intrathecal,etc., particularly for infusion), and/or other (e.g., gel, andparticularly intra-intestinal gel) formulations.

Levodopa therapy is currently standard of care for treatment of PD.

Levodopa, an aromatic amino acid, is a white, crystalline compound,slightly soluble in water, with a molecular weight of 197.2. It isdesignated chemically as (−)-L-α-amino-β-(3,4-dihydroxybenzene)propanoic acid. Its empirical formula is C₉H₁₁NO₄ and its structuralformula is:

Levodopa is a metabolic precursor not only to dopamine, but also toother neurotransmitters such as norepinephrine (noradrenaline) andepinephrine (adrenaline), both of which are, like dopamine, members ofthe catecholamine class.

Levodopa dosing and administration, particularly to subjects sufferingfrom PD, can present challenges. Before individuals develop clinicalsymptoms of PD, they will already have lost 50 to 60% of the dopamineneurons in the brain, resulting in a corresponding reduction ofapproximately 70 to 80% in dopamine concentration. In early disease,surviving neurons are still able to take up levodopa, store it asdopamine, and slowly release it over time in a continuous and relativelyconstant fashion despite fluctuating plasma levodopa levels due to theshort half-life of levodopa and the frequently unpredictable intestinalabsorption of the oral medicament. With progressive disease, however,more dopamine neurons die and this buffering capacity is lost.

With time patients therefore begin to notice that the beneficial effectsof levodopa last a few hours and then diminish or wear off, a phenomenonknown as motor fluctuations. As more dopamine neurons are lost, apatient's clinical response will more closely mirror fluctuations inblood levodopa concentrations, and eventually the levodopa response maylast only 1 or 2 hours to then wear off Due to the loss of the bufferingcapacity, the dopamine receptors will be exposed to fluctuating dopamineconcentrations resulting from fluctuating plasma levodopa levels. Whenthe levodopa-derived dopamine concentration in the brain is too high,the patient experiences dyskinesias (turning movements), and when thebrain dopamine concentration is too low, PD symptoms return. Thiscreates a therapeutic window that progressively narrows over time. Oncea patient exhibits dyskinesias, the addition of more dopamine medicationwill increase dyskinesias, whereas a reduction in dopamine medicationwill increase the off time, where PD symptoms return.

The pulsatile dopamine stimulation obtained with oral levodopaformulations is only somewhat reduced with traditional sustained releaseoral levodopa formulations. Alternative formulations and dosingstrategies continue to be explored in hopes of improving effectivelevodopa administration. The present disclosure provides technologiesfor achieving improved levodopa administration, in particular incombination with a DDI and a COMT inhibitor, specifically by providingcompositions and methods that achieve controlled exposure to each ofthese agents with surprising benefit to the subject. Additionally, insome embodiments, the present disclosure provides combinationcompositions (e.g., compositions that include each of levodopa, a DDI,and a COMT inhibitor [particularly entacapone]) that, as demonstratedherein, surprisingly improve levodopa stability, in some embodimentseven as compared with alternative formulations of the same three agents.

In some embodiments, in accordance with the present invention, levodopamay be administered orally. In some embodiments, in accordance with thepresent invention, levodopa may be administered intra-intestinally.

In some embodiments, in accordance with the present invention, levodopamay be administered in a tablet format. In some embodiments, inaccordance with the present invention, levodopa may be administered in agel format. In some particular embodiments, levodopa may be administeredintra-intestinally in a gel format.

Various formats for administration of levodopa, and compositionsthereof, are known in the art. Some such compositions include particularinhibitors of enzymes associated with the metabolic degradation oflevodopa. For example, PARCOPA® tablets contain both levodopa andcarbidopa, and are characterized by rapid disintegration on the tonguethat does not require water to aid dissolution or swallowing; SINEMET®and SINEMET® CR are sustained-release tablets containing levodopa andcarbidopa; KINSON® tablets contain both levodopa and carbidopa; MADOPAR®tablets contain levodopa and benserazide hydrochloride; and STALEVO® aretablets containing levodopa, carbidopa and entacapone.

Additionally, DUODOPA® is an intestinal gel containing a combination oflevodopa and carbidopa in a ratio of 4 to 1 that is described asproviding continuous intestinal infusion of levodopa. Use of this gelformat has been reported to reduce motor fluctuations and increase “on”time for patients (e.g., with advanced PD), relative to that observedwith oral formulations. It is believed that motor fluctuations andhyper-diskinesias are reduced in patients receiving DUODOPA® (relativeto those receiving oral therapy) because the plasma concentrations oflevodopa are kept at a steady level within a therapeutic window.DUODOPA® is administered via an inserted tube directly into theduodenum. Levodopa is absorbed quickly and effectively from theintestine through a high capacity transport system for amino acids.Levodopa has the same bioavailability (81-98%) when administered via theDUODOPA® gel as when administered in a tablet. However, variation inplasma levodopa/dopamine concentration within an individual isconsiderably smaller when levodopa is administered via the DUODOPA® gel(as compared with via a tablet); it has been proposed that such reducedvariation may be attributable to continuous intestinal administration inachieved by DUODOPA® gel, which avoids influence of gastric emptyingrate on absorption rate. With an initial high morning dose of DUODOPA®intestinal gel, the therapeutic plasma level of levodopa/dopamine isreached within 10-30 minutes.

Particular available pharmaceutical compositions of levodopa, includingSTALEVO® tablets, are described in, for example, U.S. Pat. Nos.6,500,867 B1 and 6,797,732 B2. Oral pharmaceutical compositionscomprising levodopa, carbidopa and entacapone are disclosed in WO2008/053297, WO 2012/147099, US 2006/0222703, and WO 2009/098661.Certain gel compositions of levodopa, and in particular intra-intestinalgel formats such as DUODOPA® are described, for example, in U.S. Pat.No. 5,635,213 and EP 0670713 B1.

Prescribing information for PARCOPA® indicates that it is supplied inthree strengths: PARCOPA® 25/100, containing 25 mg of carbidopa and 100mg of levodopa; PARCOPA® 10/100, containing 10 mg of carbidopa and 100mg of levodopa; and PARCOPA® 25/250, containing 25 mg of carbidopa and250 mg of levodopa. Inactive ingredients are aspartame, citric acid,crospovidone, magnesium stearate, mannitol, microcrystalline cellulose,natural and artificial mint flavor and sodium bicarbonate. PARCOPA®10/100 and 25/250 also contain FD&C blue #2 HT aluminum lake. PARCOPA®25/100 also contains yellow 10 iron oxide. PARCOPA® is indicated in thetreatment of the symptoms of idiopathic Parkinson's disease (paralysisagitans), postencephalitic parkinsonism, and symptomatic parkinsonismwhich may follow injury to the nervous system by carbon monoxideintoxication and/or manganese intoxication. PARCOPA® is indicated inthese conditions to permit the administration of lower doses of levodopawith reduced nausea and vomiting, with more rapid dosage titration, witha somewhat smoother response, and with supplemental pyridoxine (vitaminB6). Recommended dosing involves initiation with one tablet of PARCOPA®25/100 three times a day. This dosage schedule provides 75 mg ofcarbidopa per day. Dosage may be increased by one tablet every day orevery other day, as necessary, until a dosage of eight tablets ofPARCOPA® 25/100 a day is reached. If PARCOPA® 10/100 is used, dosage maybe initiated with one tablet three or four times a day. However, thiswill not provide an adequate amount of carbidopa for many patients.Dosage may be increased by one tablet every day or every other day untila total of eight tablets (2 tablets q.i.d.) is reached.

Prescribing information provided with SINEMET® tablets describes them as“a combination of carbidopa and levodopa” and indicates for “thetreatment of Parkinson's disease”. SINEMET® tablets contain 25 mg ofcarbidopa and 100 mg of levodopa, and are dosed three times a day.Dosage may be increased by one tablet every day or every other day, asnecessary, to a maximum daily dose of eight tablets. SINEMET® should notbe administered to a subject otherwise exposed to levodopa; SINEMET®dosing should not be initiated until at least twelve hours after otheradministration of levodopa has been discontinued.

Prescribing information for KINSON® tablets indicates that they contain100 mg of levodopa and 25 mg of anhydrous cabidopa. The tablets alsocontain the following inactive ingredients: cellulose-microcrystalline,starch-maize, sodium starch glycollate, talc-purified, povidone,magnesium stearate, quinoline yellow CI 47005. KINSON® tablets areapproved for the treatment of PD and Parkinson's syndrome. They are saidto be useful in relieving many of the symptoms of Parkinsonism,particularly rigidity and bradykinesia, and are also reported tofrequently be helpful in the management of tremor, dysphagia,sialorrhoea, and postural instability associated with Parkinson'sdisease and syndrome. As with many other levodopa/carbidopa combinationproducts, KINSON® is not recommended for administration to patientsreceiving other levodopa therapy; levodopa administration should bediscontinued at least 12 hours prior to initiation of therapy withKINSON®. Titrated dosing is recommended, so that dose is tailored toeach individual patient, though it is noted that peripheral dopaminedecarboxylase is saturated by carbidopa at approximately 70-100 mg perday and that patients receiving less than this amount are more likely toexperience nausea and vomiting.

According to its prescribing information, MADOPAR® is described as “amedicine used in Parkinson's disease” that contains “benserazidehydrochloride/levodopa”. MADOPAR® tablets contain 50 mg of levodopa and12.5 mg of benserazide hydrochloride; recommended dosing is four toeight capsules a day.

Prescribing information provided with STALEVO® tablets describes them as“combination of carbidopa, levodopa and entacapone” and indicates theyare for use in “the treatment of Parkinson's disease”. STALEVO® tabletscontain 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone;maximum recommended dosing is six tablets within a 24-hour period.

Prescribing information provided with DUOPOPA® indicates that the gelcontains 20 mg of levodopa and 5 mg of carbidopa monohydrate per 1 mL ofgel. Inactive ingredients include carmellose sodium and water purified.DUOPOPA® is approved in the United States for the treatment of advancedidiopathic Parkinson's disease with severe motor fluctuations despiteoptimized oral treatment. It is recommended that a positive clinicalresponse to DUOPOPA® administered via a temporary nasoduodenal tube beconfirmed before a permanent percutaneous endoscopic gastrostomy (PEG)tube is inserted. DUOPOPA® also may be delivered directly to patient'ssmall intestine. DUOPOPA® is intended for continuous daytime intestinaladministration. Administration with a portable pump (specifically, theCADD-legacy DUOPOPA® pump (CE 0473)) directly into the duodenum by apermanent tube via percutaneous endoscopic gastrostomy (PEG) with anouter transabdominal tube and an inner intestinal tube is recommended,particularly for long term administration. Alternatively a radiologicalgastrojejunostomy may be considered if PEG is not suitable for anyreason. It is recommended that a temporary nasoduodenal tube be used tofind out if the patient responds favourably to this method of treatmentand to adjust the dose before treatment with a permanent tube isstarted. Dose is typically adjusted to an optimal clinical response forthe individual patient, which means maximizing the functional ON-timeduring the day by minimizing the number of OFF episodes and the time OFF(bradykinesia) and minimizing ON-time with disabling dyskinesia. It isrecommended that, at least initially, DUOPOPA® be given initially asmonotherapy (i.e., administered to a subject not simultaneouslyreceiving other therapy).

In some embodiments, the present disclosure provides and/or utilizes apharmaceutical gel composition for intra-intestinal administration oflevodopa. In some embodiments, such a composition comprises about 10mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml,about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50 mg/ml, about 55mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml, about 75 mg/ml,about 80 mg/ml, about 85 mg/ml, about 90 mg/ml, about 95 mg/ml, about100 mg/ml, about 105 mg/ml, about 110 mg/ml, about 115 mg/ml, about 120mg/ml, about 125 mg/ml, about 130 mg/ml, about 135 mg/ml, about 140mg/ml, about 145 mg/ml, or about 150 mg/ml of levodopa. In someembodiments, such a composition comprises about, 10 mg/ml to about 150mg/ml, 10 mg/ml to about 140 mg/ml, 10 mg/ml to about 130 mg/ml, 10mg/ml to about 120 mg/ml, 10 mg/ml to about 110 mg/ml, 10 mg/ml to about100 mg/ml, about 10 mg/ml to about 90 mg/ml, about 10 mg/ml to about 85mg/ml, about 10 mg/ml to about 80 mg/ml, about 10 mg/ml to about 75mg/ml, about 10 mg/ml to about 70 mg/ml, about 10 mg/ml to about 65mg/ml, about 10 mg/ml to about 60 mg/ml, about 10 mg/ml to about 55mg/ml, about 10 mg/ml to about 50 mg/ml, or about 20 mg/ml to about 50mg/ml, of levodopa.

In some embodiments, the present disclosure may provide or utilize apharmaceutical composition for oral administration of levodopa. In someembodiments, such a composition comprises about 50 mg, about 75 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 275 mg, or about 300 mg of levodopa.

Dopamine Decarboxylase Inhibitor (DDI)

Levodopa has a short half-life in the body, 30 to 60 minutes, and uponintake of levodopa alone, more than 90% is metabolized to dopaminebefore levodopa reaches the brain. Thus, many protocols foradministering levodopa involve administration of large doses, which thenlead to high extracerebral concentrations of dopamine that may often beaccompanied by nausea and other adverse side-effects. To increase thebioavailability of levodopa, and reduce its side-effects, levodopa istherefore usually administered concurrently with a dopaminedecarboxylase inhibitor (DDI), typically carbidopa(L-2-hydrazino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid) orbenserazide (DL-2′-(2,3,4-trihydroxybenzyl) serine hydrazide), whichinhibits the conversion of levodopa to dopamine outside the brain, andwhich does not cross the blood-brain barrier.

Carbidopa

Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is awhite, crystalline compound, slightly soluble in water, with a molecularweight of 244.2. It is designated chemically as(−)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acidmonohydrate.

Carbidopa often exists and/or is utilized in monohydrate form, which hasa molecular weight of 226.3. Its empirical formula is C₁₀H₁₄N₂O₄×H₂O,and its structural formula is:

In many embodiments, reference to an amount of carbidopa by weight orweight percent may be understood as the amount found in that weight (orweight percent) of carbidopa monohydrate (i.e., may be or be understoodas an amount equivalent to the recited weight of carbidopa monohydrate).

Carbidopa is available in a variety of formats for administration topatients. For example, carbidopa is marketed as an oral tablet under thename Lodosyn. Lodosyn tablets contain 25 mg of carbidopa and areindicated for use with carbidopa-levodopa or with levodopa in thetreatment of the symptoms of idiopathic Parkinson's disease (paralysisagitans), postencephalitic parkinsonism, and symptomatic parkinsonism,which may follow injury to the nervous system by carbon monoxideintoxication and/or manganese intoxication. In particular, Lodosyn isfor use with carbidopa-levodopa in patients for whom the dosage ofcarbidopa-levodopa provides less than adequate daily dosage (usually 70mg daily) of carbidopa. Lodosyn is particularly said to be for use withlevodopa in the occasional patient whose dosage requirement of carbidopaand levodopa necessitates separate titration of each medication. It hasbeen reported that use of Lodosyn with carbidopa-levodopa or withlevodopa to permit the administration of lower doses of levodopa withreduced nausea and vomiting, more rapid dosage titration, and with asomewhat smoother response that that otherwise observed withadministration of the relevant format/regimen of levodopa. However, itis noted that patients with markedly irregular (“on-off”) responses tolevodopa have not been shown to benefit from the addition of carbidopa.Lodosyn should be dosed by titration. Most patients are said to respondto a 1:10 proportion of carbidopa and levodopa, provided the dailydosage of carbidopa is 70 mg or more a day. The maximum daily dosagethat should be administered to subjects receiving Lodosyn (whether asthe only source of carbidopa or in combination with a levodopa/carbidopaproduct) should not exceed 200 mg.

As discussed above, carbidopa is also available in certain formats inwhich it is provided in combination with levodopa (e.g., oral formatsand intra-intestinal gel formats).

In some embodiments, the present disclosure provides and/or utilizes apharmaceutical gel composition (e.g., for intra-intestinaladministration) comprising a pharmaceutically active agent thatcomprises or consists of carbidopa. In some embodiments, the presentdisclosure provides and/or utilizes a pharmaceutical gel composition. Incertain embodiments, the present disclosure provides a gel composition(e.g., for intra-intestinal administration) comprising apharmaceutically active agent that comprises or consists of carbidopa incombination with a dopamine replacement agent (e.g., levodopa), a COMTinhibitor (e.g., entacapone), or both.

In some embodiments, the present disclosure provides and/or utilizes agel composition (e.g., for intra-intestinal administration) thatcomprises about 0.5 mg/ml, about 1.0 mg/ml, about 1.5 mg/ml, about 2.0mg/mg, 2.5 mg/ml, about 3.0 mg/mg, about 3.5 mg/mg, about 4.0 mg/mg,about 4.5 mg/mg, about 5 mg/ml, about 5.5 mg/mg, about 6.0 mg/mg, about6.5 mg/mg, about 7.0 mg/mg, about 7.5 mg/ml, about 8.0 mg/mg, about 8.5mg/mg, about 9.0 mg/mg, about 9.5 mg/mg, about 10 mg/ml, about 12.5mg/ml, about 15 mg/ml, about 17.5 mg/ml, or about 20 mg/ml of carbidopa.In some embodiments, such a composition comprises about 2.5 mg/ml toabout 25 mg/ml, about 2.5 mg/ml to 22.5 mg/ml, about 2.5 mg/ml to about20 mg/ml, about 2.5 mg/ml to about 17.5 mg/ml, about 2.5 mg/ml to about15 mg/ml, about 2.5 mg/ml to about 12.5 mg/ml, or about 2.5 mg/ml toabout 10 mg/ml of carbidopa.

Benserazide

Benserazide is an inhibitor of aromatic amino acid decarboxylation witha molecular weight of 257.2. It is designated chemically as(RS)-2-amino-3-hydroxy-N′-(2,3,4-trihydroxybenzyl)propanehydrazide. Itsempirical formula is C₁₀H₁₅N₃O₅ and its structural formula is:

As noted above, benserazide is included in certain commerciallyavailable pharmaceutical products, and particularly in combinationproducts (specifically MADOPAR®, discussed above, which is also marketedas PROLOPA® in certain jurisdictions) with levodopa.

In some embodiments, the present invention may utilize one or moreavailable pharmaceutical products containing benserazide. In certainembodiments, however, the present disclosure provides and/or utilizesbenserazide in a novel gel composition. In certain embodiments, thepresent disclosure contemplates intra-intestinal administration ofbenserazide, for example via an intra-intestinal gel. In someembodiments, the present disclosure provides a gel composition (e.g.,for intra-intestinal administration) comprising a pharmaceuticallyactive agent that comprises or consists of benserazide. In certainembodiments, the present disclosure provides a gel composition (e.g.,for intra-intestinal administration) comprising a pharmaceuticallyactive agent that comprises or consists of benserazide in combinationwith a dopamine replacement agent (e.g., levodopa), a COMT inhibitor(e.g., entacapone), or both.

In some embodiments, the present disclosure provides and/or utilizes apharmaceutical gel composition for intra-intestinal administration ofbenserazide. In some embodiments, such a composition comprises about 2.5mg/ml, about 5.0 mg/ml, about 7.5 mg/ml, about 10 mg/ml, about 12.5mg/ml, about 15 mg/ml, about 17.5 mg/ml, or about 20 mg/ml ofbenserazide. In some embodiments, such a composition comprises about 2.5mg/ml to about 25 mg/ml, about 2.5 mg/ml to 22.5 mg/ml, about 2.5 mg/mlto about 20 mg/ml, about 2.5 mg/ml to about 17.5 mg/ml, about 2.5 mg/mlto about 15 mg/ml, about 2.5 mg/ml to about 12.5 mg/ml, or about 2.5mg/ml to about 10 mg/ml of benserazide.

In some embodiments, the present disclosure provides and/or utilizes apharmaceutical gel composition for intra-intestinal administration ofdopamine decarboxylase inhibitors. In some embodiments, such a comprisesabout 2.5 mg/ml, about 5.0 mg/ml, about 7.5 mg/ml, about 10 mg/ml, about12.5 mg/ml, about 15 mg/ml, about 17.5 mg/ml, or about 20 mg/ml of oneor more dopamine decarboxylase inhibitors. In some embodiments, such acomposition comprises about 2.5 mg/ml to about 25 mg/ml, about 2.5 mg/mlto 22.5 mg/ml, about 2.5 mg/ml to about 20 mg/ml, about 2.5 mg/ml toabout 17.5 mg/ml, about 2.5 mg/ml to about 15 mg/ml, about 2.5 mg/ml toabout 12.5 mg/ml, or about 2.5 mg/ml to about 10.0 mg/ml of one or moredopamine decarboxylase inhibitors.

In some embodiments, the present disclosure may provide or utilize apharmaceutical composition for oral administration of DDIs. In somecomposition comprises about 12.5 mg to about 75 mg of one or more DDIs.

Catechol-O-Methyltransferase (COMT) Inhibitor

In some embodiments, features of the present invention includerecognition that certain beneficial effects may be achieved and/orproblems avoided through administration of a COMT inhibitor in a gelcomposition, and particularly in an intra-intestinal gel composition,optionally in combination with one or more other active agents (e.g.,with levodopa and/or with a DDI). The present disclosure demonstrates,for example, that intra-intestinal administration of a COMT inhibitor ina pharmaceutical gel composition has particular benefit for subjectsreceiving therapy with a dopamine precursor, and particularly withlevodopa.

In some embodiments, such administration permits reduced exposure of thesubjects to levodopa relative to that required with other formats and/orregimens for administration of levodopa (e.g., alone, in combinationwith a DDI (e.g., carbidopa), and/or in a different format).

Alternatively or additionally, such administration can reduce negativeeffects (e.g., hydrazine level) in subjects receiving therapy withlevodopa and DDI (e.g., carbidopa). Still further, the presentdisclosure specifically demonstrates improved storage stabilitycharacteristics for certain gel compositions when a COMT inhibitor(e.g., entacapone) is included in the composition.

In some aspects, the present disclosure establishes such improvedstorage stability characteristics for pharmaceutical gel compositionsthat contain levodopa and carbidopa; that is, the present disclosuredemonstrates such improved storage stability characteristics when a COMTinhibitor (e.g., entacapone) is included in a gel composition comprisinglevodopa and carbidopa as compared with an otherwise comparablecomposition lacking the COMT inhibitor. As will be understood by thoseskilled in the art reading the present disclosure, the findingsexemplified herein may reasonably be generalized to other combinationsof COMT inhibitors, DDI inhibitors and/or dopamine precursors.

Still further, the present disclosure documents a surprising feature ofcertain gel compositions comprising a dopamine precursor (e.g.,levodopa), a DDI (e.g., carbidopa), and a COMT inhibitor (e.g.,entacapone) in that intra-intestinal administration of such compositionsenhance bioavailability of the dopamine precursor to an extent greaterthan observed with comparable combinations in other formats.

In patients with PD, levodopa may after peripheral administration alsobe directly metabolized by the enzyme catechol-O-methyltransferase(COMT) to 3-O-methyldopa (3-OMD; 3-methoxy-4-hydroxy-L-phenylalanine).In order to further increase the levodopa half-life in the body, acatechol-O-methyltransferase inhibitor, typically entacapone((2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-prop-2-enamide),has been administered in conjunction with levodopa and carbidopa.Entacapone as a catechol-O-methyltransferase (COMT) inhibitor isdescribed in the European patent No. 0444899 B1. Another COMT inhibitorused as an adjunct to levodopa/carbidopa medication is tolcapone(3-dihydroxy-4′-methyl-5-nitrobenzophenone). A recently developed COMTinhibitor for add-on therapy to levodopa is opicapone(2,5-dichloro-3-[5-(3,4-dihydroxy-5-nitrophenyl]-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide).

Entacapone, an inhibitor of catechol-O-methyltransferase (COMT), is anitro-catechol-structured compound with a molecular weight of 305.3. Thechemical name of entacapone is(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide.Its empirical formula is C₁₄H₁₅N₃O₅ and its structural formula is:

In some embodiments, the present disclosure provides and/or utilizes apharmaceutical gel composition for intra-intestinal administration ofentacapone. In some embodiments, such a composition comprises about 5.0mg/ml, about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml,about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50mg/ml, about 55 mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml,or about 75 mg/ml of entacapone. In some embodiments, such a compositioncomprises about 5.0 mg/ml to about 100 mg/ml, about 5.0 mg/ml to about90 mg/ml, about 5.0 mg/ml to about 85 mg/ml, about 5.0 mg/ml to about 80mg/ml, about 5.0 mg/ml to about 75 mg/ml, about 5.0 mg/ml to about 70mg/ml, about 5.0 mg/ml to about 65 mg/ml, about 5.0 mg/ml to about 60mg/ml, about 5.0 mg/ml to about 55 mg/ml, about 5.0 mg/ml to about 50mg/ml, about 5.0 mg to about 45 mg/ml, about 5.0 mg/ml to about 40 mg/mlof entacapone.

In some embodiments, the present disclosure may provide or utilize apharmaceutical composition for oral administration of entacapone. Insome embodiments, such a composition comprises about 12.5 mg to about250 mg of entacapone.

Opicapone is an inhibitor of catechol-O-methyltransferase (COMT) with amolecular weight of 413.17. The chemical name of opicapone is(4Z)-4-[3-(2,5-dichloro-4,6-dimethyl-1-oxidopyridin-1-ium-3-yl)-2H-1,2,4-oxadiazol-5-ylidene]-2-hydroxy-6-nitrocyclohexa-2,5-dien-1-one.Its empirical formula is C₁₅H₁₀Cl₂N₄O₆ and its structural formula is

In some embodiments, the present disclosure provides and/or utilizes apharmaceutical gel composition for intra-intestinal administration ofopicapone. In some embodiment, such a composition comprises about 0.5mg/ml, about 1.0 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5mg/ml, about 3.0 mg/ml, about 4.0 mg/ml, about 5.0 mg/ml, about 6.0mg/ml, about 7.0 mg/ml, about 8.0 mg/ml, about 9.0 mg/ml, or about 10mg/ml of opicapone. In some embodiments, such a composition comprisesabout 0.5 mg/ml to about 10 mg/ml, about 0.5 mg/ml to about 9.0 mg/ml,about 0.5 mg/ml to about 8.5 mg/ml, about 0.5 mg/ml to about 8.0 mg/ml,about 0.5 mg/ml to about 7.5 mg/ml, about 0.5 mg/ml to about 7.0 mg/ml,about 0.5 mg/ml to about 6.5 mg/ml, about 0.5 mg/ml to about 6.0 mg/ml,about 0.5 mg/ml to about 5.5 mg/ml, or about 0.5 mg/ml to about 5.0mg/ml of opicapone.

In some embodiments, the present disclosure may provide or utilize apharmaceutical composition for oral administration of opicapone. In someembodiments, such a composition comprises about 10 mg to about 100 mg ofopicapone.

Tolcapone is an inhibitor of catechol-O-methyltransferase (COMT) with amolecular weight of 273.2. The chemical name of opicapone is(3,4-Dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone. Its empiricalformula is C₁₄H₁₁NO₅ and its structural formula is

In some embodiments, the present disclosure provides and/or utilizes apharmaceutical gel composition for intra-intestinal administration oftolcapone. In some embodiments, such a composition comprises about 5.0mg/ml about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml,about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50mg/ml, about 55 mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml,or about 75 mg/ml of tolcapone. In some embodiments, such a compositioncomprises about 10 mg/ml to about 100 mg/ml, about 10 mg/ml to about 90mg/ml, about 10 mg/ml to about 85 mg/ml, about 10 mg/ml to about 80mg/ml, about 10 mg/ml to about 75 mg/ml, about 10 mg/ml to about 70mg/ml, about 10 mg/ml to about 65 mg/ml, about 10 mg/ml to about 60mg/ml, about 10 mg/ml to about 55 mg/ml, about 10 mg/ml to about 50mg/ml, or about 5.0 mg/ml to about 40 mg/ml of tolcapone.

In some embodiments, the present disclosure may provide or utilize apharmaceutical composition for oral administration of tolcapone. In someembodiments, such a composition comprises about 12 mg to about 75 mg oftolcapone.

Intra-Intestinal Compositions

Certain attempts have been made to improve stability of levodopa inpharmaceutical compositions and/or to improve consistency of itsdelivery, for example in hopes of reducing one or more side effects(e.g., dyskinesias) of levodopa administration and/or reducing frequencyand/or length of “off periods”.

For example, as discussed above, infusion technologies have beendeveloped (particularly for treatment of for late stage PD patients),according to which levodopa is continuously administered throughinfusion via an external pump and directly into the part of the smallintestine (e.g., duodenum or jejunum) where most of the levodopa isabsorbed. Such an approach is believed to provide more continuous plasmalevels, which in turn are intended to achieve reduction in both offperiods and dyskinesias. It is also known that continuous delivery canreduce motor complications, as such complications are due tonon-physiological, and intermittent administration of the drug. (Olanowet al, www.thelancet.com/neurology, Vol 13, P 141-149, 2014) However,due to the low aqueous solubility of levodopa and carbidopa, largevolumes of levodopa/carbidopa solutions had to be used which werecumbersome and impractical to the patient.

Other technologies that have been developed include, for example, aliquid composition of levodopa and carbidopa which is stabilized bycitric acid and EDTA, as described in EP 1670450 B1.

Furthermore, as discussed above, an intra-intestinal gel technology hasbeen developed in which micronized levodopa and carbidopa are suspendedin a methyl cellulose thickener gel, and the composition is delivereddirectly to the duodenum by intraduodenal infusion. Specifically, anintra-intestinal gel containing 20 mg/ml levodopa and 5 mg/ml carbidopafor intraduodenal infusion is marketed under the trade name DUODOPA®.Such pharmaceutical formulations for intraduodenal administration aredisclosed in U.S. Pat. No. 5,635,213 and EP 0670713 B1. Long term 24hours intestinal administration of levodopa/carbidopa is disclosed in WO2007/138086 A1. DUODOPA® has been reported to display/achieveimprovements in chemical stability of levodopa in an aqueous medium ascompared with that observed for other levodopa formats. DUODOPA® hasalso been reported to have beneficial particle distribution (e.g.,absence of sedimentation) characteristics, and to be useful in thetreatment of PD.

The present disclosure provides certain compositions and therapeuticregimens that show improvements even relative to DUODOPA®. In someembodiments, for example, provided compositions (including specificallypharmaceutical gel compositions that, like DUODOPA®) include bothlevodopa and carbidopa further include a COMT inhibitor (e.g.,entacapone). Thus, in some embodiments, the present disclosure providesgel compositions (e.g., for intra-intestinal administration) thatcomprise a pharmaceutically active agent that comprises or consists of aCOMT inhibitor (e.g., entacapone) in combination with a dopaminereplacement agent (e.g., levodopa), a DDI (e.g., carbidopa), or both.

Among other things, the present disclosure identifies the source of aproblem with DUODOPA® as a pharmaceutical format for the storage and/oradministration of levodopa. Specifically, the present disclosureappreciates that DUODOPA® has relatively short shelf-life (e.g., 15weeks in refrigerator (e.g., 2-8° C.), 16 hours in room temperature(e.g., 25° C.)). DUODOPA® is even recommended to be stored frozen toextend its shelf-life. For example, one drug cassette can be only usedup to 16 hours.

It has been reported that intraduodenal administration of DUODOPA® maysometimes be combined with oral administration of entacapone, which canincrease bioavailability of levodopa.(https://.medicines.org.uk/emc/medicine/20786, last visited Sep. 3,2015) However, the present disclosure identifies the source of a problemwith such strategies, given that plasma drug level fluctuates due tounpredictable intestinal absorption of the oral medicament as discussedabove. Thus, the present disclosure appreciates that it can bechallenging to provide consistent result with the oral administration ofentacapone, and therefore further appreciates that improved strategiesfor administration of a triple combination of levodopa, a DDI, andentacapone are desirable and can be developed.

A stable liquid composition that comprises levodopa, carbidopa andentacapone together with arginine and optionally meglumine for interalia intraduodenal administration is disclosed in WO 2012/066538.

The present disclosure encompasses the insight that certain beneficialeffects may be achieved by providing and utilizing certain gelcompositions (e.g., for intra-intestinal administration) that comprise aCOMT inhibitor (e.g., entacapone), and furthermore, that certain suchgel compositions, e.g., wherein the pharmaceutically active agentincluded in the compositions comprises or consists of a combination of adopamine replacement agent (e.g., levodopa), a DDI (e.g., carbidopa),and a COMT inhibitor (e.g., entacapone) have certain unexpected valuableproperties as compared with other available formats including some orall of these agents. For example, among other things, the presentdisclosure demonstrates that provided three-agent gel compositions canprovide stable plasma drug level and long shelf-life as compared withother formats.

In some embodiments, compositions provided by the present inventiondiffer from the previously known levodopa/carbidopa intra-intestinal gel(in the following for brevity “LCIG”), such as DUODOPA®. Among otherthings, in some embodiments, provided compositions are characterized,for example, by improved stability of included active agents as comparedwith other compositions (e.g., DUODOPA®) including such agents. In someembodiments, provided compositions may contain and/or may be dosed sothat a patient receives a lower or less frequent dose of one or moreincluded active agents than is present in and/or occurs with otheravailable compositions containing the agent(s).

In some particular embodiments, provided compositions are or includeintra-intestinal gels and include levodopa, a DDI, and a COMT inhibitor.In some particular embodiments, provided compositions areintra-intestinal gel compositions that are substantially similar to oneor more reference compositions described in one or more ofintra-intestinal gels and/or marketed as DUODOPA®, but differ from suchreference compositions in that they include a COMT inhibitor, such asentacapone, within them.

In comparison with an LCIG, inclusion of a COMT inhibitor (e.g.,entacapone, opicapone, tolcapone) in accordance with certain embodimentsof the present invention, may reduce the daily levodopa intake, by about10-30%, thereby reducing the risk of the patient developinglevodopa-related side effects, such as dyskinesia and motor fluctuation.

Reduction of the levodopa intake is also highly desirable. More severeneurographic abnormalities have been reported in patients treated withLCIG infusion than in orally treated patients. The degree of theseverity of the neuropathic change correlating with increased dose oflevodopa.

In some embodiments, administration of COMT inhibitors (e.g.,entacapone, tolcapone) via the intra-intestinal gel composition may leadcontrolled entacapone or tolcapone delivery. In some embodiments,separate oral administration of entacapone or toplcapone may be combinedwith LCIG administration.

In some embodiments, the present disclosure may provide or utilize apharmaceutical composition of DDIs and levodopa. In some embodiments,the weight ratio of DDIs to levodopa in such a composition is about 1:20to about 1:2, about 1:15 to about 1:2, about 1:10 to about 1:2, about1:8 to about 1:4, about 1:5 to about 1:3, about 1:15 to about 1:8, orabout 1:12 to about 1:0. In some embodiments, the weight ratio of DDIsto levodopa in such a composition is about 1:12, about 1:11, about 1:10,about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about1:3, or about 1:2.

In some embodiments, the present disclosure may provide or utilize apharmaceutical composition of COMT inhibitors and levodopa. In someembodiments, the weight ratio of COMT inhibitors to levodopa in such acomposition is about 10:1 to about 0.5:1, about 8:1 to about 4:1, about5:1 to about 3:1, about 5:1 to about 0.5:1, about 3:1 to about 0.5:1, orabout 2:1 to about 0.5:1. In some embodiments, the weight ratio of COMTinhibitors to levodopa in in such a composition is about 10:1, about9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1,about 2:1, about 1:1, or about 0.5:1.

In some embodiments, a provided gel format is a semi-solid compositionwherein the pharmaceutically active ingredients (e.g., levodopa, DDI andCOMT inhibitor) are present in the form of particles suspended in anaqueous carrier having a viscosity of at least about 300 mPas, at amoderate shear rate, as defined herein.

In some embodiments, particles of active ingredients in anintra-intestinal gel composition may have a maximum particle size notexceeding about 80 μm, about 60 μm, about 40 μm, or about 20 μm.Particles may be micronized. Further, an aqueous carrier has a viscosityof at least 300 mPas, usually in the range of 300 to 5000 Pas, at amoderate shear rate (between 20 and 500 s⁻¹).

In some embodiments, a carrier may have plastic or pseudoplastic natureso that the viscosity will be lowered during agitation, whereby theliquid aqueous carrier will be easier to pump.

In some embodiments, an aqueous carrier is usually a dispersion orsolution of a pharmaceutically acceptable colloid, a water-soluble orwater-swellable colloid of polysaccharide type, including, for instancecellulose, methyl cellulose, ethyl cellulose, carboxymethyl celluloseand salts thereof, xanthan gum, carrageenan, or a synthetic polymer,e.g., polyvinylpyrrolidone or polyacrylic acid, combinations thereof.

In some embodiments, viscosity of a gel composition may be sufficientlyhigh to carry drug load of active ingredients without a tendency ofsedimentation. In some embodiments, viscosity may not be too high sothat it should be possible to pump gel, for example, with an ambulatorypump (e.g., with reasonable battery consumption).

In certain embodiments, a suitable viscosity may be obtained byadjusting the molecular weight of colloid used into a suitable range,such as by adjusting the degree of polymerization. In some embodiments,the viscosity may be adjusted by selecting a suitable concentration ofcolloid in an aqueous system.

In some embodiments, viscosity of an intra-intestinal gel compositionmay be at least about 1800 mPas, or in the range of about 2200 to about4500 mPas.

In some embodiments, intra-intestinal gel compositions further compriseother components. For example, in some embodiments, such compositionsmay comprise one or more pharmaceutically inactive components. In someembodiments, other components may be selected from the group consistingof metal chelators, preservatives, excipients, surfactants, emollients,buffers, and combinations thereof.

In some embodiments, intra-intestinal gel compositions further compriseor more dopamine agonists (e.g., bromocriptine, cabergoline, pergolide,pramipexole, ropinirole, rotigotine, apomorphine, dihydroergocristinemesylate, piribedil). Dopamine agonists activate dopamine receptors inthe absence of dopamine, mimicking the functions of dopamine in thebrain.

In some embodiment, intra-intestinal gel compositions further compriseone or more monoamine oxidase type B (MAO-B) inhibitors (e.g.,rasagiline, selegiline). Monoamine oxidase type B (MAO-B) breaks downdopamine in the brain, catalyzing the oxidative deamination of biogenicand xenobiotic amines.

In some embodiment, intra-intestinal gel compositions further compriseone or more anticholinergics (e.g., antihistamines, tropine, tropinederivatives (e.g., ethers of tropine)). Anticholinergics block thebinding acetylcholine to its receptor in nerve cells, therefore inhibitsacetylcholine in nervous system.

In some embodiment, intra-intestinal gel compositions further compriseone or more glutamate antagonist.

In some embodiment, intra-intestinal gel compositions further compriseone or more amantadine or amantadine derivatives.

An intra-intestinal gel composition may be prepared by mixing a carrierwith water to form a gel and then dispersing finely active components(e.g., levodopa, a DDI, and a COMT inhibitor) in the aqueous carrierusing methods and apparatus which are well-known to those skilled in theart. The prepared formulations are then dispensed into suitablecontainers for intra-intestinal, such as duodenal, administration.

An intra-intestinal gel composition may be administered via intestinaladministration (e.g., directly into the intestine (e.g., duodenum orjejunum)), by a direct jejunostomy, or via a percutaneous endoscopicgastrostomy.

In some embodiments, a gel is administered with a portable pump (e.g.,peristaltic or syringe type). An exemplary peristaltic pump is that soldunder the trade name CADD-Legacy DUODOPA® pump (Smiths Medical, Minn.,U.S.A.). A gel may be contained in a cassette, pouch or vial that isattached to the pump to create a delivery system. The delivery system isconnected to a duodenal tube or ajejunum tube for intra-intestinaladministration. An example of a syringe type delivery system is theportable pump sold under the trade name Cane Crono Infusion Pump(Applied Medical Technology Ltd., Cambridge, U.K.).

In some embodiments, an intra-intestinal gel of the present inventionmay be administered continuously over a period of up to about 16 hoursabout 18 hours, about 20 hours, about 22 hours, about 24 hours per day.In some embodiments, an intra-intestinal gel of the present inventionmay be administered continuously for more than one day, a week, or amonth.

In some embodiments, an intra-intestinal gel composition is administeredso that it delivers a desired amount of one or more of its active agentsin a day (e.g., in a 24 hour period).

Stability

One feature of certain embodiments of the present invention relates tothe storage stability, or shelf life, of a pharmaceutical composition,and particularly of an intra-intestinal gel composition.

The shelf life of the prior art intra-intestinal gel LCIG (e.g.,DUODOPA®) in refrigerated condition is basically determined by thedegradation of carbidopa, and more specifically the level of thedegradation product hydrazine which is considered to be genotoxic.

While levodopa has been found to be relatively stable in the prior artLCIG as well as in intra-intestinal gel compositions of the presentinvention, carbidopa has been found to degrade about 50 percent quickerin a corresponding intra-intestinal gel composition which additionallycontains entacapone.

In some embodiments, levodopa/carbidopa/entacapone gel compositions ofthe invention provide surprising properties that hamper the formation ofthe final carbidopa degradation product (e.g., hydrazine). In someembodiments, compositions of the present invention may have anadvantageously lowered hydrazine level (e.g., less than about 20 ppm, orless than about 30 ppm) after long term storage in refrigeratedcondition compared with the prior art intra-intestinal gel LCIG (e.g.,DUODOPA®). In some embodiments, compositions for the present inventionmay have about 50% less hydrazine level compared with the prior artintra-intestinal gel LCIG (e.g., DUODOPA®).

In some embodiments, in such a gel composition entacapone will functionnot only as a COMT inhibitor but also as a hydrazine-formation inhibitorin degradation of carbidopa.

An increase of the stability of the levodopa/carbidopa/entacaponecomposition of the invention to have, for instance, a stability of about10 weeks, about 15 weeks, about 20 weeks or about 25 weeks in arefrigerated condition, when active ingredients should still have ameaningful therapeutic effect, may be accomplished by different means,separately, or, optionally, by two or more of them in combination. Insome embodiments, an increase of the stability of thelevodopa/carbidopa/entacapone composition of the invention to have, forinstance, a stability of about 18 hours, about 20 hours, about 22 hours,about 24 hours, about 26 hours, about 28 hours, or about 30 hours inroom temperature (e.g., 25° C.).

According to some embodiments of invention, the stability of anintra-intestinal gel composition may be increased by adjusting the pH ofthe gel composition to not be higher than about 5.7 (i.e. equal to orlower than 5.7).

Generally, the stability of active substances (primarily carbidopa) in agel composition increases as the pH is lowered. On the other hand,however, the stability of a gel per se decreases with lower pH (beingdestabilized by breaking down of the viscosity). Further, too low a pHvalue of a gel composition is detrimental to the patient's intestine.

According to some embodiments of invention, it has been found thatincreased storage stability with regard to active substances as well asto a gel structure and to the sensitivity of the patient's intestine isachieved by careful selection of the pH to be within an optimum range offrom about 4.5 to about 5.7, preferably 4.5 to 5.5, for example about5.0.

In some embodiments, acidic adjustment of the pH may be effected by amineral acid, such as hydrochloric acid, or an organic acid, for examplecitric acid or citric buffer.

Alternatively, or in addition to pH stabilization, stabilization of agel composition may be effected by oxygen removal which may be done bywell known methods, typically by purging with nitrogen gas.

Yet an alternative way of stabilizing an intra-intestinal gelcomposition is to introduce one or more antioxidants, e.g., ascorbicacid or citric acid, into a gel. Other antioxidants that may be used mayreadily be selected by a person skilled in the art from commonly knownantioxidants.

Storage of a gel composition in a light reducing container, such as analuminum bag, has also been found to have some positive effect on thedegradation of carbidopa and entacapone.

In some embodiments, an intra-intestinal gel composition of theinvention has a pH of about 5, is deoxygenized with nitrogen gas, and ispreferably provided in a light protected container.

Heavy metals are known to catalyse the degradation of carbidopa. Whileprior art levodopa/carbidopa formulations have been shown to bestabilized by EDTA, which has a great chelating property, the stabilityof the intra-intestinal gel composition of the invention hassurprisingly been found to be negatively affected by EDTA. In someembodiments, gel compositions provided by the invention are thereforepreferably free of any chelating agent.

Those of ordinary skill in the art, reading the present disclosure, willappreciate that its included demonstration of increased carbidopastability in the presence of entacapone (and specifically in thepresence of entacapone in a gel composition for intra-intestinaladministration) may well be generalizable to presence of other COMTinhibitors, and/or to contexts other than combination in a gel format asdescribed herein. Thus, in some embodiments, the present disclosureprovides gel compositions (e.g., for intra-intestinal administration)comprising a pharmaceutically active agent that comprises or consists ofcarbidopa and a COMT inhibitor, and optionally further compriseslevodopa. Furthermore, in some embodiments, the present disclosureprovides therapeutic regimens in which administration of carbidopa iscombined with administration of entacapone (e.g., in the context of agel composition for intra-intestinal administration) or other COMTinhibitor, optionally in separate compositions, may reduce hydrazinelevels (e.g., as compared with those observed under comparableconditions absent the COMT inhibitor, e.g., entacapone), with beneficialeffects for patients.

Combination Therapy

As described herein, the present invention provides technologies thatinvolve and/or achieve combination therapy with (a) a dopaminereplacement agent; (b) one or more DDIs and (c) one or more COMTinhibitors. As described herein, in many embodiments, the presentdisclosure relates to administration of individual agents or combinationagents for which certain therapeutic regimens and formats are alreadyknown. In some embodiments, insights embodied in the present disclosureprovide compositions and/or dosing regimens that contain or includereduced dosing (e.g., in daily amount, total amount over a selectedperiod, and/or frequency of dosing) relative to such known regimensand/or formats.

In certain embodiments, as described herein, each of (a) a dopaminereplacement agent (b) a DDI; and (c) a COMT inhibitor are administeredsimultaneously, and even in a single composition (e.g., in anintra-intestinal gel composition as described herein). Teachingsincluded herein provide those of ordinary skill in the art with insightsand technologies (e.g., compositions and methods) that are not limitedto the specific exemplified embodiments.

For example, teachings provided herein demonstrate to those of skill inthe art, for example, that the (a) a dopamine replacement agent (b) aDDI; and (c) a COMT inhibitor might, in certain embodiments, beadministered in separate compositions. In some embodiments, each may bein a distinct composition. In some embodiments, two may be together in asingle composition while the third is in a separate composition. To givebut one specific example, those skilled in the art, reading the presentdisclosure, would appreciate that co-administration of DUODOPA® with aseparate intra-intestinal gel composition comprising entacapone, and/oranother COMT inhibitor, might be desirable.

Of course, those skilled in the art will immediately be aware that notall advantages documented herein may be achieved, or achieved to thesame level, in all such formats. That is, particular advantages may beattributable, at least in part, to co-localization of all three agentsin a single composition. However, those skilled in the art will alsorecognize that significant benefit may also be achieved even withoutsuch co-localization. For example, co-administration (whethersubstantially simultaneous or separated in time but nonethelessachieving exposure of the patient, and optionally the same site withinthe patient [e.g., the duodenum] to all three agents), for example, ofseparate gels, may well provide significant benefit relative to otheravailable therapeutic strategies.

Those of ordinary skill in the art, reading the present disclosure willparticularly appreciate that, in some embodiments, depending on one ormore features of the particular utilized (a) dopamine replacement agents(b) DDI; and (c) a COMT inhibitors, distinct dosing patterns might bebeneficial in some contexts. For instance, different agents within aparticular class may have different half-lives and/or otherpharmacologic properties, such that their timing of administrationrelative to other agents might desirably be staggered. To give but oneexample, studies have reported different pharmacokinetic andpharmacodynamic properties for different COMT inhibitors (see, forexample, Forsberg et al., JPET 304:498, 2003-02-01) and have reported,for instance that tolcapone has a longer duration of action and a betterbrain penetration than entacapone. Specifically, Forsberg et al reportthat:

-   -   “After intravenous administration (3 mg/kg), the elimination        half-life (t_(1/2β)) of entacapone (0.8 h) was clearly shorter        than that of tolcapone (2.9 h). The striatum/serum ratio of        tolcapone was 3-fold higher than that of entacapone. After a        single oral dose (10 mg/kg), both entacapone and tolcapone        produced an equal maximal degree of COMT inhibition in        peripheral tissues, but tolcapone inhibited striatal COMT more        effectively than did entacapone. After the 7-day treatment (10        mg/kg twice daily), COMT activity had recovered to a level of 67        to 101% of control within 8 h after the last dose of entacapone.        In tolcapone-treated animals, there was still extensive COMT        inhibition present in peripheral tissues, and the degree of        inhibition was higher than that attained after a single dose.        The pharmacokinetic-pharmacodynamic modeling revealed that a        plateau of COMT inhibition near the maximal attainable        inhibition was reached already by plasma concentrations below        2000 ng/ml, both with entacapone and tolcapone. Entacapone and        tolcapone inhibited equally rat liver COMT in vitro with K_(i)        values of 10.7 and 10.0 nM, respectively,”        and conclude that their results” suggest that peripheral COMT        inhibitor is inhibited continuously when tolcapone is dosed at        12-h intervals, but this was not seen with entacapone.”

One of ordinary skill in the art, aware of these differences and readingthe present disclosure would appreciate that, for example, it might bedesirable to dose tolcapone less frequently than entacapone. Given thatthe present disclosure demonstrates, among other things, particularutility of intra-intestinal gel administration of COMT inhibitors, andalso demonstrates certain advantages of compositions that contain eachof (a) a dopamine replacement agent (b) a DDI; and (c) a COMT inhibitor,those of ordinary skill in the art would appreciate that the disclosureprovides combination compositions that include tolcapone (e.g.,compositions that include each of levodopa, carbidopa, and tolcapone),optionally in a gel format, for example for intra-intestinaladministration, and would also appreciate that, in some embodiments, itmight be desirable to include a lower ratio of COMT inhibitor to otheractive agents when the COMT inhibitor is tolcapone as compared withentacapone. Alternatively, comparable ratios might be preserved, butless frequent dosing utilized, optionally for example interspersed withadditional dosing of a composition that contained on the (a) dopaminereplacement agents and (b) DDI.

Alternatively or additionally, one skilled in the art, reading thepresent disclosure, will appreciate the extent to which its teachingsmay be applied to and/or combined with administration of one or more ofthe (a) dopamine replacement agents (b) DDI; and (c) COMT inhibitor inthe context of an already-available format (e.g., as described herein).Thus, for example, in some embodiments, therapeutic regimens provided bythe present disclosure may utilize, for example, intra-intestinaladministration of a gel composition comprising a COMT inhibitor (e.g.,entacapone) in combination with (a) dopamine replacement agents (e.g.,levodopa) and/or (b) a DDI (e.g., carbidopa) in the context of anavailable commercial format. In some such embodiments, route, timing,and/or amount of any individual dose (and/or of total doses) of thecommercial format may be different when combined with the,intra-intestinal administration of a gel composition comprising a COMTinhibitor as provided herein.

Still further, one of ordinary skill in the art will readily appreciatethat, in some embodiments, combination therapy as described herein, inaccordance with which a patient receives therapy with each of (a) adopamine replacement agent; (b) one or more DDIs and (c) one or moreCOMT inhibitors may be further combined with one or more othertherapies/therapeutic modalities. Just to name a few, in someembodiments, provided therapy is administered in combination with one ormore anticholinergics (e.g., antihistamines, topine, and/or estersthereof etc. and combinations thereof), one or more glutamateantagomists, and/or one or more amantadine derivatives. In someembodiments, one or more such agents are included in an intra-intestinalgel as described herein.

Bioavailability

In some embodiments, the present invention encompasses the insight thatadministering a combination of levodopa, a DDI, and a COMT inhibitor toa subject, wherein one or more of the agents in the combination isadministered by intra-intestinal administration of a pharmaceutical gel,provides unexpected improvement of one or more pharmacokineticproperties (e.g., area under curve (AUC), bioavailability (e.g.,absolute bioavailability, relative bioavailability), half-life, etc.) ofone or more active agents.

Among other things, the present disclosure demonstrates the surprisingdiscovery that provided compositions and/or methodologies can achievesignificant improvement in bioavailability of a dopamine replacementagent (e.g., levodopa). Specifically, prior reports of combinationtherapy with the three-component combination of (a) levodopa, (b)carbidopa, and (c) entacapone in a single tablet can increasebioavailability of levodopa about 10% to about 30% as compared with anotherwise comparable tablet containing (a) levodopa and (b) carbidopabut lacking (c) entacapone. (see, for example, Summary of ProductCharacteristics of STALEVO®,http://www.ema.europa.edu/docs/en_GB/document_library/EPAR_-_Product_Information/human/00511/WC500057485.pdf,last visited Sep. 3, 2015) Table 1, below, summarizes certain literaturereports observed increases in levodopa bioavailability upon combinationwith COMT inhibitors:

TABLE 1 Levodopa bioavailability increase in the presence of COMTinhibitors Levodopa Reference COMT inhibitor bioavailablity increaseFine et al. 2000¹⁶ Tolcapone 33% Hobson et al. 2002²³ Tolcapone 25%Vingerhoets et al. 2002⁵³ Entacapone 20% Wenzelburger et al. 2002⁵⁶ COMTinliibitor* 30% Brodsky et al. 2003⁴ COMT inhibitor* 20% Esselink et al.2004¹² Entacapone 20% Evans et al. 2004¹³ Entacapone 33% Reimer et al.2004⁴⁷ COMT inhibitor* 30% Möller et al. 2005³⁷ Entacapone 30% Deuschiet al. 2006¹⁰ Entacapone 33% Ondo et al. 2006⁴² COMT inhibitor* 10%Katzenschlager et al. 2008²⁶ Entacapone 33% Cabrini et al. 2009⁵Entacapone 33% Peralta et al. 2009⁴⁶ Entacapone 20% Fan et al. 2009¹⁴COMT inliibitor* 25% *The type of COMP inhibitor has not provided.

As can be seen with reference to the Examples section below, andparticularly with reference to Example 4, the present disclosuredocuments the surprising finding that certain inventive gel compositions(e.g., formulated for intra-intestinal administration) including apharmaceutically active agent that comprises or consists of each of (a)a dopamine replacement agent; (b) a DDI; and (a) COMT inhibitor canachieve a dramatically larger increase in levodopa bioavailability,indeed more than 40%, 45%, 50%, or even 55%, as an average increase of55% (an improvement within the range of 1.5-3.0 fold) was observed, evenin the single study described therein.

In light of these remarkable findings, one of ordinary skill in the artwill appreciate that the present disclosure establishes thatcompositions and/or combinations can be identified, developed, provided,and/or characterized that also achieve improvement in one or morepharmacokinetic or pharmacodynamic properties of levodopa (and/orpotentially one or more other dopamine replacement agents). The presentdisclosure provides technologies for achieve such identification,development, provision and/or characterization.

For example, in certain embodiments, those of ordinary skill in the artmay follow guidance presented in Example 4 (viewed in context of therest of the present specification) to test any of a variety of differentDDI and/or COMT inhibitor agents, and combinations (e.g., differentratios, etc.) thereof, and assess their effect(s) on bioavailabilityand/or other parameters (e.g., stability, half-life, AUC over a selectedperiod of time, etc.) of one or more dopamine replacement agents whenadministered to a model organism or human (and/or as evaluated in one ormore appropriate models thereof).

Thus, the present disclosure provides, among other things, compositionscomprising a dopamine replacement agent, a DDI and a COMT inhibitor,which is characterized by an improvement in one or more pharmacokineticand/or pharmacodynamic features of the dopamine replacement agent whenassessed in an appropriate system as compared with an appropriatereference composition. In some embodiments, an appropriate referencecomposition is an otherwise comparable composition lacking the COMTinhibitor, or including a different COMT, or including the same COMTinhibitor in a different amount (whether absolute or relative to thedopamine replacement agent, the DDI, or both). In some embodiments, anappropriate reference composition is an otherwise comparable compositionlacking the DDI, or including a different DDI, or including the same DDIin a different amount (whether absolute or relative to the dopaminereplacement agent, the COMT inhibitor, or both).

In some embodiments, an appropriate improvement has a magnitude of atleast 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%,or more. In some embodiments, an appropriate improvement has a magnitudeof at least 1.5×, 2.0×, 2.5×, 3.0×, 3.5×, 4.0×, 4.5×, 5.0×, 5.5×,6.0×6.5×, 7.0×, 7.5×, 8.0×, 8.5×, 9.0×, 9.5×, 10×, or more.

In the following, non-limiting embodiments of an intra-intestinal gelcomposition of the present invention and comparative experimentstherewith will be described.

EXAMPLES Example 1: Compositions

In the following, experiments will be described performed with anembodiment of intra-intestinal gel composition according to the presentinvention, below referred to as “LECIGON™”, and with the prior artcommercial levodopa/carbidopa intra-intestinal gel, DUODOPA®, belowreferred to as “LCIG”, as well as with modified LECIGON™ compositionsfor stability tests. The compositions of LCIG and LECIGON™ are given inTables 2 and 3 below.

TABLE 2 Exemplary composition of LCIG Substance Amount Micronizedlevodopa 2% (w/w) (20 mg/ml) Micronized carbidopa 0.5% (w/w) (5.0 mg/ml)NaCMC 2.92% (w/w) Purified water 94.58% (w/w)

TABLE 3 Exemplary Compositions of LECIGON ™ Substance Amount Micronizedlevodopa 2% (w/w) (20 mg/ml) Micronized carbidopa 0.5% (w/w) (5.0 mg/ml)Micronized entacapone 2% (w/w) (20 mg/ml) NaCMC 2.92% (w/w) Purifiedwater 92.58% (w/w)

15 exemplary small scale batches as described in Table 4 weremanufactured as described below and filled into syringes for initial andstability evaluation in various storage and use conditions. The batchsize of the experiments was 100 to 500 g. In Table 4, API is activepharmaceutical ingredient, L is levodopa, C is carbidopa, and E isentacapone.

TABLE 4 Exp. API (mg/g) pH Formulation 1 L: 20, C: 5 6.1 Reference 2 L:20, C: 5, E: 20 5.7 Reference + Entacapone 3 L: 20, C: 5, E: 20 5.60.05% EDTA 4 L: 20, C: 5, E: 20 5.60 0.5% citric acid (NaOH for pHadjustment) 5 L: 20, C: 5, E: 20 5.75 0.1% ascorbic acid (NaOH for pHadjustment) 6 L: 20, C: 5, E: 20 5.03 Low pH (target pH 5.0) 7 L: 20, C:5, E: 20 7.0 High pH (target pH 7.0) 8 L: 20, C: 5, E: 20 5.7 Aluminiumbag (composition 2) 9 L: 20, C: 5 — Reference with 0.5% citric acid +0.05% EDTA 10 L: 20, C: 5, E: 20 5.6 0.5% citric acid + 0.05% EDTA 11 L:20, C: 5, E: 20 5.86 Reference LECIGON ™ 12 L: 20, C: 5, E: 20 5.5 0.5%citrate buffer (citric acid/sodium citrate) 13 L: 20, C: 5, E: 20 5.00.5% citrate buffer (low pH) 14 L: 20, C: 5, E: 20 5.75 0.1% ascorbicAcid + 0.05% EDTA 15 L: 20, C: 5, E: 20 5.86 Deoxydation using N₂

Example 2: Manufacturing Process

The exemplary manufacturing process of intra-intestinal gel samples tobe tested is described below.

-   1) Sodium carboxymethyl cellulose was added to purified water in a    Pyrex beaker during homogenization for 1-2 minutes until a lump free    viscous solution was achieved.-   2) The active ingredients levodopa, carbidopa and entacapone were    added and homogenized until a homogenous suspension was achieved.-   3) Additional excipients as described in Table 3 above were added    during homogenization until dissolved.-   4) If needed, the pH was adjusted to the target by addition of    sodium hydroxide or hydrochloric acid solution during mixing.-   5) Manual filling of the suspension into syringes.

The process equipment used for manufacturing of the experimental batchesincluded a Silverson L5M Homogenizer (Silverson Machines Ltd., Chesham,U.K.), and a IKA Janke & Kunkel RW28W Mixer (IKA Works GmbH, Staufen,Germany).

The following analytical equipment was used for physical analysis and inprocess controls during the manufacturing:

pH-meter—Mettler Toledo Seven Compact™ with Inlab Micro electrode(Mettler-Toledo Inc., Columbia, Ohio, U.S.A.).

Viscometer—Brookfield DV-I™ Prime with small sample adapter (BrookfieldEngineering, Middleborough, Mass., U.S.A.).

HPLC—Agilent 1100 with DAD detector and cooled injector; OpenLAB CDSChemstation C.01.05 (Agilent Technologies Inc., Santa Clara, Calif.,U.S.A.).

Example 3: Stability Tests

This example demonstrates stability of intra-intestinal gels undervarious conditions.

3.1. Stability of Unstabilized LECIGON™ Vs LCIG

The stability of unstabilized LECIGON™ was compared with that of LCIGwith regard to the stability of carbidopa, especially its degradationproduct hydrazine which is considered to be genotoxic. Hydrazine isformed in equal molar number as 3,4-dihydroxyphenylacetone (DHPA), whichis easier to measure and was therefore used as reference in this as wellas in the other experiments below. The results are shown in Table 5below.

TABLE 5 DHPA (area % of carbidopa) 5 days at 10 days at Exp. Formulation25° C. 25° C. 1 LCIG: 20/5 mg/ml levodopa/carbidopa 3.08 5.1 suspension2 LECIGON ™: 20/5/20 mg/ml 4.76 7.65 levodopa/carbidopa/entacaponesuspension Comparing 1 with 2 +55% +50%

As shown in Table 5, carbidopa degrades about 50% quicker in the triplelevodopa-carbidopa-entacapone gel suspension (LECIGON™) compared to acorresponding levodopa-carbidopa gel suspension (LCIG).

3.2. Stabilization of LECIGON™

Stabilization experiments with LECIGON™ with regard to carbidopa,levodopa and entacapone were performed in an accelerated stability studyat 25° C. for 12 days. As reference product, LECIGON™ having nostabilizing modification was used. In addition to determination of DHPA,an additional carbidopa degradation product,3,4-dihydroxyphenylpropionic acid (DHPPA), as well as an (so far)unidentified degradation product of entacapone were measured.

The following stabilizing modifications of the LECIGON™ composition weretested, the corresponding experimental compositions (“Exp.”) in Table 4above being given within parentheses:

1. Varied pH (Exp. 6, 7)

2. Addition of anti-oxidant

-   -   a) 0.1% ascorbic acid (Exp. 5)    -   b) 0.5% citrate buffer (Exp. 12)    -   c) 0.5% citric acid (Exp. 4)        3. Removal of oxygen    -   nitrogen gas (Exp. 15)        4. Removal of metal ions    -   0.05% EDTA (Exp. 3)        5. Combination of reduced pH and anti-oxidant (Exp. 13)        6. Combination of anti-oxidant and removal of oxygen    -   a) 0.1% ascorbic acid and 0.05% EDTA (Exp. 14)    -   b) 0.5% citric acid and 0.05% EDTA (Exp. 10)        7. Enclosure in an aluminium bag (Exp. 8).

The results are presented in Table 6 below. The results are ranked withrespect to reduction of hydrazine (DHPA, RRT 7.1). RRT 8.5 is DHPPA, andRRT 11.8 is a degradation product of entacapone. Levodopa was stable inall combinations and is therefore not included in the table. In thetable, “Carb” is carbidopa, and “Ent” is entacapone.

TABLE 6 Formulation Degradation products from LECIGON ™ = 20/5/20Carbidopa Ent. mg/ml of levodopa/ DHPA RRT RRT RRT Exp.carbidopa/entacapone 7.1 8.5 11.8 Comment 6 LECIGON ™ + Low pH −73% −77% −76% Reduction in pH has the (pH 5.0) clearest positive impact onboth Carb and Ent 5 LECIGON ™ + 0.1% −42%  −10% −25% Ascorbic acid has aclear ascorbic acid (NaOH for positive impact on the stabilitypH-adjustment) of both Carb and Ent 15 LECIGON ™ −37%  −12% −42%Deoxygenized suspension with deoxygenized with N₂ N₂ has a clearpositive impact on both Carb and Ent 12 LECIGON ™ + 0.5%  1% −13% −23%Citrate buffer has a positive citrate buffer (citric impact on both,more so om acid/sodium citrate) Ent 4 LECIGON ™ + 0.5%  2% −17%  −9%Citrate acid has a slight citric acid (NaOH for positive impact on bothCarb pH-adjustment) and Ent 3 LECIGON ™ + 0.05% 20%  32%  38% EDTA has anegative impact EDTA on the stability of both Carb and Ent 7 LECIGON ™ +High pH 109%  713% 703% Increased pH has the clearest (pH 7.0) negativeimpact on both Carb and Ent 13 LECIGON ™ + 0.5% −9% −78% −74% Citratebuffer in a combination citrate buffer (pH 5) with a low pH has apositive effect on both Carb and Ent. However the combination does notoffer any benefits compared to only reducing pH. 14 LECIGON ™ + 0.1% 10%−49% −45% Ascorbic acid in combination ascorbic Acid + 0.05% with EDTAhas a positive EDTA effect on Ent and one degradation product form Carb,however negative on DHPA. 8 LECIGON ™ + −2%  −8% Aluminium bag has minorimpact on Aluminium bag both Carb and Ent, likely due to (formulation 2)reduced light exposure. 10 LECIGON ™ + 0.5% 29%  85% A combination ofboth citric acid and citric acid + 0.05% EDTA has a negative impact onboth EDTA carbidopa and entacapone3.3. pH Impacting Effect on the Stability of LECIGON™

pH was measured using a pH (glass) electrode. Indicated pH refersmeasurement for the final product.

As shown in Table 6 above, pH has the greatest impact on the stabilityof both carbidopa and entacapone, its impact, however, being reducedwith a reduced pH. The level of degradation products formed at the endof an accelerated stability study, 10 days at 25° C., at different pH ofthe gel suspension are shown in FIG. 1 (Carbidopa: DHPA), FIG. 2(Carbidopa: RRT 8.5=DHPPA), and FIG. 3 (RRT 11.8).

3.4. Viscosity

While, as demonstrated above, a lower pH has a positive impact on thestability of both carbidopa and entacapone, however, a lower pH breaksdown the viscosity of the NaCMC gel. FIG. 4 shows the level of reducedviscosity at end of an accelerated stability study, 12 days at 25° C.,at different pH of the gel suspension.

3.5. Stability of LECIGON™, Summary

According to the test results obtained, the final formulation shouldhave a reduced pH. A reduced pH, however, has two main drawbacks.Firstly, it breaks down the viscosity which destabilizes the suspension(sedimentation), the lower the pH is the quicker the gel breaks down,and secondly, a low pH may cause an irritation of the intestine at thesite of administration. A viscosity reduction of maximum 1000 cP after12 days would be acceptable which corresponds to a pH of about 4.9-5.0.

A pH of about 5 will likely not cause any irritation at the site ofadministration considering, among other things, the low daily volume ofLECIGON™ administered (100 ml) compared to the about 10 liter of gastricjuice passing the intestine per day, the gastric juice in addition beingbuffered.

Therefore, a suspension having a pH of about 5, stabilized with citricacid, deoxygenized with N₂, and having a container with light protectionwill likely give the best possible stability. A suitable alternative isa suspension having a pH of about 5, stabilized with ascorbic acid,deoxygenized with N₂, and having a container with light protection.

Heavy metals are known to catalyse the degradation of carbidopa. It iswell known that EDTA has a great chelating property and that EDTA hasshown stabilizing effects on carbidopa in a levodopa—carbidopaformulation. It was therefore surprising that EDTA had a negative impacton the stability of the present intra-intestinal gel formulation.

3.6 Long Term Storage Stability in Refrigerated Condition

A. Stability of LECIGON™ vs LCIG

The stabilities of samples of pH-stabilized LECIGON™ (pH 5.5) and LCIGwere subjected to a 20 weeks storage test in refrigerated condition at2-8° C. with regard to hydrazine formation. The hydrazine levels of thesamples were measured at 14, 16 and 20 weeks. The results are shown inFIG. 5, where the upper curve indicates the hydrazine levels for LCIGand the lower curve the hydrazine levels for LECIGON™.

Since as demonstrated in Table 4 above, carbidopa degrades quicker inLECIGON™ than in LCIG, the level of hydrazine would theoretically behigher than in LCIG. The lower hydrazine levels obtained for LECIGON™therefore indicate that the formation of hydrazine is inhibited by thepresence of entacapone in the gel formulation.

B. Stability of LECIGON™ at Different pH Values

The stability of LECIGON™ samples stabilized at pH 5.5 or 5.0,respectively, with regard to hydrazine formation was studied in asimilar 20 weeks storage test in refrigerated condition as in A above.The hydrazine levels of the samples were measured at 8, 14 and 20 weeks.The results are shown in FIG. 6, the upper curve showing the pH levelsat pH 5.5, and the lower curve hydrazine levels at 5.0. As could beexpected from the stability experiments on LECIGON™ presented furtherabove, the hydrazine level at 20 weeks is considerably lower for theLECIGON™ formulation at pH 5.0.

Example 4: Pharmacokinetic Studies of LECIGON™

Two samples were used for pharmacokinetic studies: a gel with levodopaand carbidopa (DUODOPA® containing 20 mg/ml of levodopa, and 5 mg/ml ofcarbidopa), and the other gel with levodopa, carbidopa and entacapone(LECIGON™ containing 20 mg/ml of levodopa, 5 mg/ml of carbidopa, and 20mg/ml of entacapone). All 11 patients received both treatmentsrandomized, two days in a row. All patients were already on the DUODOPA®treatment and optimized on DUODOPA® treatment (individual doses).LECIGON™ doses were reduced to 80% of the optimized DUODOPA® dose toavoid patient becoming too hyperkinetic. Plasma concentration wasmeasured at hour (from start of treatment) 0, 0.5, 1, 1.5, 2, 2.5, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 14.5, 15, 15.5, 16, 16.5, 17 and 24hours.

The bioavailability of levodopa is expected to increase with 10-30%(Summary of Product Characteristics of STALEVO®,http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000511/WC500057485.pdf,last visited Sep. 3, 2015) if it is given in combination with entacaponeand carbidopa in a tablet form. As shown in Table 7 and FIG. 7,continuously administered LECIGON™ increased AUC of levodopa 55% onaverage, which is higher than the expected increase (e.g., 10-30%) asdiscussed above. LECIGON™ enables entacapone to increase levodopa's AUCefficiently. Without wishing to be bound by any particular theory, it isproposed that, as entacapone has a longer t_(1/2) life than levodopa,entacapone inhibits catechol-O-methyltransferase until all levodopa ismetabolized.

TABLE 7 LECIGON ™ DUODOPA ® AUC 0-24 hours AUC 0-24 hours Subject (h *ng/ml per mg (h * ng/ml per mg Increased AUC/dose ID of levodopa) oflevodopa) with LECIGON ™ 105 33.3 28.2 18% 104 45.3 30.2 50% 106 72.943.6 67% 109 69.3 42.4 64% 111 67.9 40.2 69% 102 98.2 61.6 59% 110 35.228.3 25% 103 39.6 26.0 52% 108 54.2 33.3 63% 101 49.1 29.5 67% 107 74.943.5 72% Average 58.2 37.0 55%

The present invention is not limited to the above-described preferredembodiments. Various alternatives, modifications and equivalents may beused. Therefore, the above embodiments should not be taken as limitingthe scope of the invention, which is defined by the appending claims.

The invention claimed is:
 1. A pharmaceutical composition forintra-intestinal administration, comprising a dopamine replacement agentselected from levodopa, melevodopa, etilevodopa and combinationsthereof, a dopamine decarboxylase inhibitor (DDI) wherein the dopaminedecarboxylase inhibitor is carbidopa, benzerazide or combinationthereof, and a catechol-O-methyltransferase (COMT) inhibitor selectedfrom entacapone, tolcapone, opicapone and combinations thereof; andwherein the pharmaceutical composition comprises about 1.0 to about 15%(w/w) micronized dopamine replacement agent, about 0.1 to about 2.0%(w/w) micronized DDI, about 1.0 to about 5.0% (w/w) micronized COMTinhibitor, and about 1.0 to about 7.5% (w/w) sodium carboxymethylcellulose.
 2. The pharmaceutical composition of claim 1, wherein: thepharmaceutical composition has a pH of about 5.7 or less; thepharmaceutical composition is deoxygenized; the pharmaceuticalcomposition further comprises an antioxidant; the pharmaceuticalcomposition is free from metal chelating agent; and/or thepharmaceutical composition is provided in a light-protected container.3. The pharmaceutical composition of claim 1, wherein the compositionhas a pH of about 4.5 to about 5.5.
 4. The pharmaceutical composition ofclaim 1, wherein the pharmaceutical composition further comprises anantioxidant, wherein said antioxidant is ascorbic acid or citric acid.5. The pharmaceutical composition of claim 1, wherein the dopaminereplacement agent, the DDI, and the COMT inhibitor are in the form ofparticles, wherein the particles are suspended in an aqueous carrier,and have a particle size no greater than 80 μm; and the aqueous carrierhas a viscosity of at least 300 mPas at a moderate shear rate.
 6. Thepharmaceutical composition of claim 5, wherein the aqueous carriercomprises a polysaccharide selected from the group consisting ofcellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose,salts thereof, and combinations thereof.
 7. The pharmaceuticalcomposition of claim 6, wherein the aqueous carrier comprises sodiumcarboxymethyl cellulose.
 8. The pharmaceutical composition of claim 5,wherein the pH of the pharmaceutical composition is greater than about5.0, and the viscosity of the aqueous carrier after 12 days at 25° C. isat least about 300 mPas at a moderate shear rate.
 9. The pharmaceuticalcomposition of claim 1, wherein the weight ratio of DDI to COMTinhibitor is about 1:10 to about 1:2, or about 1:5 to about 1:3.
 10. Thepharmaceutical composition of claim 1, wherein the weight ratio of COMTinhibitor to dopamine replacement agent is about 10:1 to about 2:1, or5:1 to 3:1.
 11. A pharmaceutical composition for intra-intestinaladministration, comprising about 20 mg/ml of dopamine replacement agent,about 5 mg/ml of DDI, and about 20 mg/ml of COMT inhibitor.
 12. Thepharmaceutical composition of claim 11, wherein the pharmaceuticalcomposition has a pH of about 4.5 to about 5.5.
 13. The pharmaceuticalcomposition of claim 11, wherein the dopamine replacement agent, theDDI, and the COMT inhibitor are in the form of particles, wherein theparticles are suspended in an aqueous carrier, and have a particle sizeno greater than 80 μm; and the aqueous carrier has a viscosity of atleast 300 mPas at a moderate shear rate.
 14. The pharmaceuticalcomposition of claim 13, wherein the aqueous carrier comprises apolysaccharide selected from the group consisting of cellulose, methylcellulose, ethyl cellulose, carboxymethyl cellulose, salts thereof, andcombinations thereof.
 15. The pharmaceutical composition of claim 14,wherein the aqueous carrier comprises sodium carboxymethyl cellulose.16. The pharmaceutical composition of claim 11, wherein the pH of thepharmaceutical composition is greater than about 5.0, and the viscosityof the aqueous carrier after 12 days at 25° C. is at least about 300mPas at a moderate shear rate.
 17. A method of treating aneurodegenerative disease comprising administering intra-intestinally apharmaceutical composition of claim 1 to a subject in need thereof. 18.A method of treating Parkinson's Disease, Alzheimer's Disease, orHuntingtop's Disease comprising administering intra-intestinally apharmaceutical composition of claim 1 to a subject in need thereof. 19.The pharmaceutical composition according to claim 1 wherein thecomposition is in the form of a gel suspension.
 20. A method of treatinga neurodegenerative disease comprising administering intra-intestinallya pharmaceutical composition of claim 15 to a subject in need thereof.21. A method of treating Parkinson's Disease, Alzheimer's Disease, orHuntington's Disease comprising administering intra-intestinally apharmaceutical composition of claim 15 to a subject in need thereof. 22.The pharmaceutical composition according to claim 15 wherein thecomposition is in the form of a gel suspension.